HLA BINDING PEPTIDES AND THEIR USES

Abstract: The present invention provides the means and methods for selecting immunogenic peptides and the immunogenic peptide compositions capable of specifically binding glycoproteins encoded by HLA alleles and inducing T cell activation in T cells restricted by the allele. The peptides are useful to elicit an immune response against a desired antigen.

Description: HLA BINDING PEPTIDES AND THEIR USES ' REFERENCE TO RELATED APPLICATIONS The present application is a continuation-in-part of USSN 08/205,713 filed March 4, 1994. The present application is also related to USSN 09/017,735, USSN 08/753,622, USSN 08/822,382, USSN 60/013,980, USSN 08/589,108, USSN 08/454,033, USSN 08/349,177, USSN 08/073,205, and USSN 08/027,146. The present application is also related to USSN 09/017,524, USSN 08/821,739, USSN 60/013,833, USSN 08/75.8,409, USSN 08/589,107, USSN 08/451,913 and to USSN 08/347,610, USSN 08/186,266, USSN 08/159,339, USSN 09/116,061, USSN 08/103,396, USSN 08/027,746, and USSN 07/926,666. The present application is also related to USSN 09/017,743; USSN 08/753,615; USSN 08/590,298; USSN 08/452,843; USSN 09/115,400; USSN 08/344,824; and USSN 08/278,634. The present application is also related to USSN ' 08/197,484 and USSN 08/815,396. All of the above applications are incorporated herein by reference. BACKGROUND OF THE INVENTION The present invention relates to compositions and methods for preventing, treating or diagnosing a number of pathological states such as viral diseases and cancers. In particular, it provides novel peptides capable of binding selected major histocompatibility complex (MHC) molecules and inducing an immune response. MHC molecules are classified as either Class I or Class II molecules. Class II MHC molecules are expressed primarily on cells involved in initiating and sustaining immune responses, such as T lymphocytes, B lymphocytes, macrophages, etc. Class II MHC molecules are recognized by helper T lymphocytes and induce proliferation of helper T lymphocytes and amplification of the immune response to the particular immunogenic peptide that is displayed. Class I MHC molecules are expressed on almost all nucleated cells and are recognized by cytotoxic T lymphocytes (CTLs), which then destroy the antigen-bearing cells. CTLs are particularly important in tumor rejection and in fighting viral infections. The CTL recognizes the antigen in the form of a peptide fragment bound to the MHC class I molecules rather than the intact foreign antigen itself. The antigen must normally be endogenously synthesized by the cell, and a portion of the protein antigen is degraded into small peptide fragments in the cytoplasm. Some of these small peptides translocate into a pre-Golgi compartment and interact with class I heavy chains to facilitate proper folding and association with the subunit β2 icroglobulin. The peptide-MHC class I complex is then routed to the cell surface for expression and potential recognition by specific CTLs. Investigations of the crystal structure of the human MHC class I molecule, HLA-A2.1, indicate that a peptide binding groove is created by the folding of the αl and α2 domains of the class I heavy chain (Bjorkman et al., Nature 329:506 ( 1987). In these investigations, however, the identity of peptides bound to the groove was not determined. Buus et al., Science 242:1065 (1988) first described a method for acid elution of bound peptides from MHC. Subsequently, Rammensee and his coworkers (Falk et al., Nature 351:290 (1991) have developed an approach to characterize naturally processed peptides bound to class I molecules. Other investigators have successfully achieved direct amino acid sequencing of the more abundant peptides in various HPLC fractions by conventional automated sequencing of peptides eluted from class I molecules of the B type (Jardetzky, et al., Nature 353:326 (1991) and of the A2.1 type by mass spectrometry (Hunt, et al, Science 225:1261 (1992). A review of the characterization of naturally processed peptides in MHC Class I has been presented by Rδtzschke and Falk (Rδtzschke and Falk, Immunol. Today 12:447 (1991). Sette et al., Proc. Natl. Acad. Sci. USA 86:3296 (1989) showed that MHC allele specific motifs could be used to predict MHC binding capacity. Schaeffer et al., Proc. Natl. Acad. Sci. USA 86:4649 (1989) showed that MHC binding was related to immunogenicity. Several authors (De Bruijn et al., Eur. J. Immunol., 21:2963-2970 (1991); Pa er et al, 991 Nature 353:852-955 (1991)) have provided preliminary evidence that class I binding motifs can be applied to the identification of potential immunogenic peptides in animal models. Class I motifs specific for a number of human alleles of a given class I isotype have yet to be described. It is desirable that the combined frequencies of these different alleles should be high enough to cover a large fraction or perhaps the majority of the human outbred population. Despite the developments in the art, the prior art has yet to provide a useful human peptide-based vaccine or therapeutic agent based on this work. The present invention provides these and other advantages. P T/US00/04655 • 3 SUMMARY OF THE INVENTION The present invention provides compositions comprising immunogenic peptides having binding motifs for HLA-A2.1 molecules. The immunogenic peptides, which bind to the appropriate MHC allele, are preferably 9 to 10 residues in length and comprise conserved residues at certain positions such as positions 2 and 9. Moreover, the peptides do not comprise negative binding residues as defined herein at other positions such as positions 1, 3, 6 and/or 7 in the case of peptides 9 amino acids in length and positions 1, 3, 4, 5, 7, 8 and/or 9 in the case of peptides 10 amino acids in length. The present invention defines positions within a motif enabling the selection of peptides which will bind efficiently to HLA A2.1. The motifs of the inventions include peptide of 9 amino acids which have • f a first conserved residue at the second position from the N-terminus selected from the group consisting of I, V, A and T and a second conserved residue at the C-terminal position selected from the group consisting of V, L, I, A and M. Alternatively, the peptide may have a first conserved residue at the second position from the N-terminus selected from the group consisting of L, M, I, V, A and T; and a second conserved residue at the C-terminal position selected from the group consisting of A and M. If the peptide has 10 residues it will contain a first conserved residue at the second position from the N- terminus selected from the group consisting of L, M, I, V, A, and T; and a second conserved residue at the C-terminal position selected from the group consisting of V, I, L, A and M; wherein the first and second conserved residues are separated by 7 residues. Epitopes on a number of immunogenic target proteins can be identified using the peptides of the invention. Examples of suitable antigens include prostate cancer specific antigen (PSA), prostate specific membrane antigen (PSM), hepatitis B core and surface antigens (HBVc, HBVs) hepatitis C antigens, Epstein-Barr virus antigens, human immunodeficiency type-1 virus (HTVl), Kaposi's sarcoma herpes virus (KSHV), human papilloma virus (HPV) antigens, Lassa virus, mycobacterium tuberculosis (MT), p53 and murine p53 (mp53), CEA, trypanosome surface antigen (TSA), members of the tyrosinas related protein (TRP) families, and Her2/neu. The peptides are thus useful in pharmaceutical compositions for both in vivo and ex vivo therapeutic and diagnostic applications. The present invention also provides compositions comprising immunogenic peptides having binding motifs for MHC Class I molecules. The immunogenic peptides are typically between about 8 and about 11 residues and comprise conserved residues involved in binding proteins encoded by the appropriate MHC allele. A number of allele specific motifs have been identified. For instance, the motif for HLA- A3.2 comprises from the N-terminus to C-terminus a first conserved residue of L, M, I, V, S, A, T and F at position 2 and a second conserved residue of K, R or Y at the C-terminal end. Other first conserved residues are C, G or D and alternatively E. Other second conserved residues are H or F. The first and second conserved residues are preferably separated by 6 to 7 residues. The motif for HLA-A1 comprises from the N-terminus to the C-terminus a first conserved residue of T, S or M, a second conserved residue of D or E, and a third conserved residue of Y. Other second conserved residues are A, S or T. The first and second conserved residues are adjacent and are preferably separated from the third conserved residue by 6 to 7 residues. A second motif consists of a first conserved residue of E or D and a second conserved residue of Y where the first and second conserved residues are separated by 5 to 6 residues. The motif for HLA-A11 comprises from the N-terminus to the C-terminus a first conserved residue of T, V, M, L, I, S, A, G, N, C D, or F at position 2 and a C- terminal conserved residue of K, R, Y or H. The first and second conserved residues are preferably separated by 6 or 7 residues. The motif for HLA-A24.1 comprises from the N-terminus to the C- terminus a first conserved residue of Y, F or at position 2 and a C terminal conserved residue of F, I, W, M or L. The first and second conserved residues are preferably separated by 6 to 7 residues. Epitopes on a number of potential target proteins can be identified in this manner. Examples of suitable antigens include prostate specific antigen (PSA), prostate specific membrane antigen (PSM), hepatitis B core and surface antigens (HBVc, HBVs) hepatitis C antigens, malignant melanoma antigen (MAGE-1) Epstein-Barr virus antigens, human immunodeficiency type-1 virus (HTV1), papilloma virus antigens, Lassa virus, mycobacterium tuberculosis (MT), p53 and murine p53 (mp53), CEA, and Her2/neu, and members of the tyrosinase related protein (TRP) families. The peptides are thus useful in pharmaceutical compositions for both in vivo and ex vivo therapeutic and diagnostic applications. The present invention also provides compositions comprising immunogenic peptides having binding motifs for non-A HLA alleles. The immunogenic peptides are preferably about 9 to 10 residues in length and comprise conserved residues at certain positions such as proline at position 2 and an aromatic residue (e.g., Y, W, F) or hydrophobic residue (e.g., L, I, V, M, or A) at the carboxy terminus. In particular, an advantage of the peptides of the invention is their ability to bind to two or more different HLA alleles. Epitopes on a number of potential target proteins can be identified in this manner. Examples of suitable antigens include prostate specific antigen (PSA), hepatitis B core and surface antigens (HBVc, HBVs) hepatitis C antigens, malignant melanoma antigen (MAGE-1) Epstein-Barr virus antigens, human immunodeficiency type-1 virus (HΓVI), papilloma virus antigens, Lassa virus, mycobacterium tuberculosis (MT), p53, CEA, and Her2/neu. The peptides are thus useful in pharmaceutical compositions for both in vivo and ex vivo therapeutic and diagnostic applications. Definitions The term "peptide" is used interchangeably with "oligopeptide" in the present specification to designate a series of residues, typically L-amino acids, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of adjacent amino acids. The oligopeptides of the invention are less than about 15 residues in length and usually consist of between about 8 and about 11 residues, preferably 9 or 10 residues. An "immunogenic peptide" is a peptide which comprises an allele-specific motif such that the peptide will bind an MHC molecule and induce a CTL response. Immunogenic peptides of the invention are capable of binding to an appropriate HLA- A2.1 molecule and inducing a cytotoxic T cell response against the antigen from which the immunogenic peptide is derived. Immunogenic peptides are conveniently identified using the algorithms of the invention. The algorithms are mathematical procedures that produce a score which enables the selection of immunogenic peptides. Typically one uses the algorithmic score with a "binding threshold" to enable selection of peptides that have a high probability of binding at a certain affinity and will in turn be immunogenic. The algorithm is based upon either the effects on MHC binding of a particular amino acid at a particular position of a peptide or the effects on binding of a particular substitution in a motif containing peptide. A "conserved residue" is an amino acid which occurs in a significantly higher frequency than would be expected by random distribution at a particular position in a peptide. Typically a conserved residue is one where the MHC structure may provide a contact point with the immunogenic peptide. At least one to three or more, preferably two, conserved residues within a peptide of defined length defines a motif for an immunogenic peptide. These residues are typically in close contact with the peptide binding groove, with their side chains buried in specific pockets of the groove itself. Typically, an immunogenic peptide will comprise up to three conserved residues, more usually two conserved residues. As used herein, "negative binding residues" are amino acids which if present at certain positions (for example, positions 1, 3 and/or 7 of a 9-mer) will result in a peptide being a nonbinder or poor binder and in turn fail to be immunogenic i.e. induce a CTL response. The term "motif refers to the pattern of residues in a peptide of defined length, usually about 8 to about 11 amino acids, which is recognized by a particular MHC allele. The peptide motifs are typically different for each human MHC allele and differ in the pattern of the highly conserved residues and negative residues. The binding motif for an allele can be defined with increasing degrees of precision. In one case, all of the conserved residues are present in the correct positions in a peptide and there are no negative residues in positions 1,3 and/or 7. The phrases "isolated" or "biologically pure" refer to material which is substantially or essentially free from components which normally accompany it as found in its native state. Thus, the peptides of this invention do not contain materials normally associated with their in situ environment, e.g., MHC I molecules on antigen presenting cells. Even where a protein has been isolated to a homogenous or dominant band, there are trace contaminants in the range of 5-10% of native protein which co-purify with the desired protein. Isolated peptides of this invention do not contain such endogenous co- purified protein. The term "residue" refers to an amino acid or amino acid mimetic incorporated in an oligopeptide by an amide bond or amide bond mimetic. DESCRIPTION OF THE PREFERRED EMBODIMENTS T. HLA-A2.1 Motif : The present invention relates to the determination of allele-specific peptide motifs for human Class I MHC (sometimes referred to as HLA) allele subtypes, in particular, peptide motifs recognized by HLA-A2.1 alleles. These motifs are then used to define T cell epitopes from any desired antigen, particularly those associated with human viral diseases, cancers or autoiummune diseases, for which the amino acid sequence of the potential antigen or autoantigen targets is known. Epitopes on a number of potential target proteins can be identified in this manner. Examples of suitable antigens include prostate specific antigen (PSA), hepatitis B core and surface antigens (HBVc, HBVs) hepatitis C antigens, Epstein-Barr virus antigens, melanoma antigens (e.g., MAGE-1), human immunodeficiency virus (HIV) antigens, human papilloma virus (HPV) antigens, Lassa virus, mycobacterium tuberculosis (MT), p53, CEA, trypanosome surface antigen (TSA) and Her2/neu. Peptides comprising the epitopes from these antigens are synthesized and then tested for their ability to bind to the appropriate MHC molecules in assays using, for example, purified class I molecules and radioiodonated peptides and/or cells expressing empty class I molecules by, for instance, immunofluorescent staining and flow microfluorometry, peptide-dependent class I assembly assays, and inhibition of CTL recognition by peptide competition. Those peptides that bind to the class I molecule are further evaluated for their ability to serve as targets for CTLs derived from infected or immunized individuals, as well as for their capacity to induce primary in vitro or in vivo CTL responses that can give rise to CTL populations capable of reacting with virally infected target cells or tumor cells as potential therapeutic agents. The MHC class I antigens are encoded by the HLA- A, B, and C loci. HLA-A and B antigens are expressed at the cell surface at approximately equal densities, whereas the expression of HLA-C is significantly lower (perhaps as much as 10-fold lower). Each of these loci have a number of alleles. The peptide binding motifs of the invention are relatively specific for each allelic subtype. For peptide-based vaccines, the peptides of the present invention preferably comprise a motif recognized by an MHC I molecule having a wide distribution in the human population. Since the MHC alleles occur at different frequencies within different ethnic groups and races, the choice of target MHC allele may depend upon the target population. Table 1 shows the frequency of various alleles at the HLA-A locus products among different races. For instance, the majority of the, Caucasoid population can be covered by peptides which bind to four HLA-A allele subtypes, specifically HLA- A2.1, Al, A3.2, and A24.1. Similarly, the majority of the Asian population is encompassed with the addition of peptides binding to a fifth allele HLA-Al 1.2. TABLE 1 A Allele/Subtyp. 3 N(69)* A(54) , C(502) Al 10.1(7) 1.8(1) 27.4(138) A2.1 11.5(8) 37.0(20) 39.8(199) A2.2 10.1(7) 0 3.3(17) A2.3 1.4(1) 5.5(3) 0.8(4) A2.4 - - " A2.5 - - - A3.1 1.4(1) 0 0.2(0) A3.2 5.7(4) 5.5(3) 21.5(108) All.l 0 5.5(3) 0 A11.2 5.7(4) 31.4(17) 8.7(44) A11.3 0 3.7(2) 0 A23 4.3(3) - 3.9(20) A24 2.9(2) 27.7(15) 15.3(77) A24.2 - - - A24.3 - - - A25 1.4(1) - 6.9(35) A26.1 4.3(3) 9.2(5) 5.9(30) A26.2 7.2(5) - 1.0(5) A26V 3.7(2) - A28.1 10.1(7) - 1.6(8) A28.2 1.4(1) - 7.5(38) A29.1 1.4(1) - 1.4(7) A29.2 10.1(7) 1.8(1) 5.3(27) A30.1 8.6(6) - 4.9(25) A30.2 1.4(1) - 0.2(1) A30.3 7.2(5) - 3.9(20) A31 4.3(3) 7.4(4) 6.9(35) A32 2.8(2) - 7.1(36) Aw33.1 8.6(6) - 2.5(13) Aw33.2 2.8(2) 16.6(9) 1.2(6) Aw34.1 1.4(1) - - Aw34.2 14.5(10) - 0.8(4) Aw36 5.9(4) - Table compiled from B. DuPont, Immunobioloεv of HLA, Vol. I, ] Histocompa Testing 1987, Springer-Verlag, New York 1989. * N - negroid; A = Asian; C = Caucasoid. Numbers in parenthesis represent the number of individuals included in the analysis. The nomenclature used to describe peptide compounds follows the conventional practice wherein the amino group is presented to the left (the N-terminus) and t e carboxyl group to the right (the C-terminus) of each amino acid residue. In the formulae representing selected specific embodiments of the present invention, the amino- and carboxyl-terminal groups, although not specifically shown, are in the form they would assume at physiologic pH values, unless otherwise specified. In the amino acid structure formulae, each residue is generally represented by standard three letter or single letter designations. The L-form of an amino acid residue is represented by a capital single letter or a capital first letter of a three-letter symbol, and the D-form for those amino acids having D-forms is represented by a lower case single letter or a lower case three letter symbol. Glycine has no asymmetric carbon atom and is simply referred to as "Gly" or G. The procedures used to identify peptides of the present invention generally follow the methods disclosed in Falk et al., Nature 351:290 (1991), which is incorporated herein by reference. Briefly, the methods involve large-scale isolation of MHC class I molecules, typically by immunoprecipitation or affinity chromatography, from the appropriate cell or cell line. Examples of other methods for isolation of the desired MHC molecule equally well known to the artisan include ion exchange chromatography, lectin chromatography, size exclusion, high performance ligand chromatography, and a combination of all of the above techniques. In the typical case, immunoprecipitation is used to isolate the desired allele. A number of protocols can be used, depending upon the specificity of the antibodies used. For example, allele-specific mAb reagents can be used for the affinity purification of the HLA-A, HLA-B1, and HLA-C molecules. Several mAb reagents for the isolation of HLA-A molecules are available. The monoclonal BB7.2 is suitable.for isolating HLA-A2 molecules. Affinity columns prepared with these mAbs using standard techniques are successfully used to purify the respective HLA-A allele products. In addition to allele-specific mAbs, broadly reactive anti-HLA-A, B, C mAbs, such as W6/32 and B9.12.1, and one anti-HLA-B, C mAb, Bl.23.2, could be used in alternative affinity purification protocols as described in previous applications. The peptides bound to the peptide binding groove of the isolated MHC molecules are eluted typically using acid treatment. Peptides can also be dissociated from class I molecules by a variety of standard denaturing means, such as heat, pH, detergents, salts, chaotropic agents, or a combination thereof. Peptide fractions are further separated from the MHC molecules by reversed-phase high performance liquid chromatography (HPLC) and sequenced. Peptides can be separated by a variety of other standard means well known to the artisan, including filtration, ultrafiltration, electrophoresis, size chromatography, precipitation with specific antibodies, ion exchange chromatography, isoelectrofocusing, and the like. P T/US00/04655 11 Sequencing of the isolated peptides can be performed according to standard techniques such as Edman degradation (Hunkapiller, M.W., et al., Methods Enzvmol. 91, 399 [1983]). Other methods suitable for sequencing include mass spectrometry sequencing of individual peptides as previously described (Hunt, et al, Science 225:1261 (1992), which is incorporated herein by reference). Amino acid sequencing of bulk heterogenous peptides (ej^, pooled HPLC fractions) from different class I molecules typically reveals a characteristic sequence motif for each class I allele. Definition of motifs specific for different class I alleles allows the identification of potential peptide epitopes from an antigenic protein whose amino acid sequence is known. Typically, identification of potential peptide epitopes is initially carried out using a computer to scan the amino acid sequence of a desired antigen for the presence of motifs. The epitopic sequences are then synthesized. The capacity to bind MHC Class molecules is measured in a variety of different ways. One means is a Class I molecule binding assay as described in the related applications, noted above. Other alternatives described in the literature include inhibition of antigen presentation (Sette, et al., J. Immunol. 141:3893 (1991), in vitro assembly assays (Townsend, et al, Cell 62:285 (1990), and FACS based assays using mutated cells, such as RMA.S (Melief, et al., Eur. J. Immunol. 21:2963 (1991)). Next, peptides that test positive in the MHC class I binding assay are .assayed for the ability of the peptides to induce specific CTL responses in vitro. For instance, antigen-presenting cells that have been incubated with a peptide can be assayed for the ability to induce CTL responses in responder cell populations. Antigen-presenting cells can be normal cells such as peripheral blood mononuclear cells or dendritic cells (Inaba, et al., J. Exp. Med. 166:182 (1987); Boog, Eur. J. Immunol. 18:219 [1988]). Alternatively, mutant mammalian cell lines that are deficient in their ability to load class I molecules with internally processed peptides, such as the mouse cell lines RMA-S (Karre, et al.. Nature. 319:675 (1986); Ljunggren, et al, Eur. J. Immunol. 21:2963-2970 (1991)), and the human somatic T cell hybrid, T-2 (Cerundolo, et al., Nature 345:449-452 (1990)) and which have been transfected with the appropriate human class I genes are conveniently used, when peptide is added to them, to test for the capacity of the peptide to induce in vitro primary CTL responses. Other eukaryotic cell lines which could be used include various insect cell lines such as mosquito larvae (ATCC cell lines CCL 125, 126, 1660, 1591, 6585, 6586), silkworm (ATTC CRL 8851), armyworm (ATCC CRL 1711), moth (ATCC CCL 80) and Drosophila cell lines such as a Schneider cell line (see Schneider J. Embrvol. Exn. Morphol. 27:353-365 [1927]). Peripheral blood lymphocytes are conveniently isolated following simple venipuncture or leukapheresis of normal donors or patients and used as the responder cell sources of CTL precursors. In one embodiment, the appropriate antigen-presenting cells are incubated with 10-100 μM of peptide in serum-free media for 4 hours under appropriate culture conditions. The peptide-loaded antigen-presenting cells are then incubated with the responder cell populations in vitro for 7 to 10 days under optimized culture conditions. Positive CTL activation can be determined by assaying the cultures for the presence of CTLs that kill radiolabeled target cells, both specific peptide-pulsed targets as well as target cells expressing the endogenously processed form of the relevant virus or tumor antigen from which the peptide sequence was derived. Specificity and MHC restriction of the CTL is determined by testing against different peptide target cells expressing appropriate or inappropriate human MHC class I. The peptides that test positive in the MHC binding assays and give rise to specific CTL responses are referred to herein as immunogenic peptides. The immunogenic peptides can be prepared synthetically, or by recombinant DNA technology or from natural sources such as whole viruses or tumors. Although the peptide will preferably be substantially free of other naturally occurring host cell proteins and fragments thereof, in some embodiments the peptides can be synthetically conjugated to native fragments or particles. The polypeptides or peptides can be a variety of lengths, either in their neutral (uncharged) forms or in forms which are salts, and either free of modifications such as glycosylation, side chain oxidation, or phosphorylation or containing these modifications, subject to the condition that the modification not destroy the biological activity of the polypeptides as herein described. Desirably, the peptide will be as small as possible while still maintaining substantially all of the biological activity of the large peptide. When possible, it may be desirable to optimize peptides of the invention to a length of 9 or 10 amino acid residues, commensurate in size with endogenously processed viral peptides or tumor cell peptides that are bound to MHC class I molecules on the cell surface. Peptides having the desired activity may be modified as necessary to provide certain desired attributes, e.g., improved pharmacological characteristics, while increasing or at least retaining substantially all of the biological activity ' of the unmodified peptide to bind the desired MHC molecule and activate the appropriate T cell. For instance, the peptides may be subject to various changes, such as substitutions, either conservative or non-conservative, where such changes might provide for certain advantages in their use, such as improved MHC binding. By conservative substitutions is meant replacing an amino acid residue with another which is biologically and/or chemically similar, e.g., one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as Gly, Ala; Val, He, Leu, Met; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr. The effect of single amino acid substitutions may also be probed using D-amino acids. Such modifications may be made using well known peptide synthesis procedures, as described in e.g., Merrifield, Science 232:341-347 (1986), Barany and Merrifield, The Peptides. Gross and Meienhofer, eds. (N.Y., Academic Press), pp. 1-284 (1979); and Stewart and Young, Solid Phase Peptide Synthesis, (Rockford, 111., Pierce), 2d Ed. (1984), incorporated by reference herein. The peptides can also be modified by extending or decreasing the compound's amino acid sequence, e.g., by the addition or deletion of amino acids. The peptides or analogs of the invention can also be modified by altering the order or composition of certain residues, it being readily appreciated that certain amino acid residues essential for biological activity, e.g., those at critical contact sites or conserved residues, may generally not be altered without an adverse effect on biological activity. The non-critical amino acids need not be limited to those naturally occurring in proteins, such as L-α-amino acids, or their D-isomers, but may include non-natural amino acids as well, such as β-γ-δ-amino acids, as well as many derivatives of L-α-amino acids. Typically, a series of peptides with single amino acid substitutions are employed to determine the effect of electrostatic charge, hydrophobicity, etc. on binding. For instance, a series of positively charged (e.g., Lys or Arg) or negatively charged (e.g., Glu) amino acid substitutions are made along the length of the peptide revealing different patterns of sensitivity towards various MHC molecules and T cell receptors. In addition, multiple substitutions using small, relatively neutral moieties such as Ala, Gly, Pro, or similar residues may be employed. The substitutions may be homo-oligomers or hetero- oligomers. The number and types of residues which are substituted or added depend on the spacing necessary between essential contact points and certain functional attributes which are sought (e.g., hydrophobicity versus hydrophilicity). Increased binding affinity for an MHC molecule or T cell receptor may also be achieved by such substitutions, compared to the affinity of the parent peptide. In any event, such substitutions should employ amino acid residues or other molecular fragments chosen to avoid, for example, steric and charge interference which might disrupt binding. Amino acid substitutions are typically of single residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final peptide. Substitutional variants are those in which at least one residue of a peptide has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Table 2 when it is desired to finely modulate the characteristics of the peptide. TABLE 2 Original Residue Exemplary Substitution Ala Ser Arg Lys, His Asn Gin Asp Glu Cys Ser Gin Asn Glu Asp Gly Pro His Lys; Arg lie Leu; Val Leu He; Val Lys Arg; His Met Leu; He Phe Tyr; Trp Ser Thr Thr Ser Trp Tyr; Phe Tyr Trp; Phe Val He; Leu Pro Gly Substantial changes in function (e.g., affinity for MHC molecules or T cell receptors) are made by selecting substitutions that are less conservative than those in Table 2, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in peptide properties will be those in which (a) hydrophilic residue, e.g. seryl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a residue having an electropositive side chain, e.g., lysl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g. glutamyl or aspartyl; or (c) a residue having a bulky side chain, e.g. phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine. The peptides may also comprise isosteres of two or more residues in the immunogenic peptide. An isostere as defined here is a sequence of two or more residues that can be substituted for a second sequence because the steric conformation of the first sequence fits a binding site specific for the second sequence. The term specifically includes peptide backbone modifications well known to those skilled in the art. Such modifications include modifications of the amide nitrogen, the α-carbon, amide carbonyl, complete replacement of the amide bond, extensions, deletions or backbone crosslinks. See, generally, Spatola, Chemistry and Biochemistry of Amino Acids, peptides and Proteins, Vol. VII (Weinstein ed., 1983). Modifications of peptides with various amino acid mimetics or unnatural amino acids are particularly useful in increasing the stability of the peptide in vivo. Stability can be assayed in a number of ways. For instance, peptidases and various biological media, such as human plasma and serum, have been used to test stability. See, e.g.. Verhoef et al., Eur. J. Drug Metab. Pharmacokin. 11:291-302 (1986). Half life of the peptides of the present invention is conveniently determined using a 25% human serum (v/v) assay. The protocol is generally as follows. Pooled human serum (Type AB, non-heat inactivated) is delipidated by centrifugation before use. The serum is then diluted to 25% with RPMI tissue culture media and used to test peptide stability. At predetermined time intervals a small amount of reaction solution is removed and added to either 6% aqueous trichloracetic acid or ethanol. The cloudy reaction sample is cooled (4°C) for 15 minutes and then spun to pellet the precipitated serum proteins. The presence of the peptides is then determined by reversed-phase HPLC using stability- specific chromatography conditions. The peptides of the present invention or analogs thereof which have CTL stimulating activity may be modified to provide desired attributes other than improved serum half life. For instance, the ability of the peptides to induce CTL activity can be enhanced by linkage to a sequence which contains at least one epitope that is capable of inducing a T helper cell response. Particularly preferred immunogenic peptides/T helper conjugates are linked by a spacer molecule. The spacer is typically comprised of relatively small, neutral molecules, such as amino acids or amino acid mimetics, which are substantially uncharged under physiological conditions. The spacers are typically selected from, e.g., Ala, Gly, or other neutral spacers of nonpolar amino acids or neutral polar amino acids. It will be understood that the optionally present spacer need not be comprised of the same residues and thus may be a hetero- or homo-oligomer. When present, the spacer will usually be at least one or two residues, more usually three to six residues. Alternatively, the CTL peptide may be linked to the T helper peptide without a spacer. The immunogenic peptide may be linked to the T helper peptide either directly or via a spacer either at the amino or carboxy terminus of the CTL peptide. The amino terminus of either the immunogenic peptide or the T helper peptide may be acylated. Exemplary T helper peptides include tetanus toxoid 830-843, .influenza 307- 319, malaria circumsporozoite 382-398 and 378-389. In some embodiments it may be desirable to include in the pharmaceutical compositions of the invention at least one component which primes CTL. Lipids have been identified as agents capable of priming CTL in vivo against viral antigens. For example, palmitic acid residues can be attached to the alpha and epsilon amino groups of a Lys residue and then linked, e.g., via one or more linking residues such as Gly, Gly- Gly-, Ser, Ser-Ser, or the like, to an immunogenic peptide. The lipidated peptide can then be injected directly in a micellar form, incorporated into a liposome or emulsified in an adjuvant, e.g., incomplete Freund's- adjuvant. In a preferred embodiment a particularly effective immunogen comprises palmitic acid attached to alpha and epsilon amino groups of Lys, which is attached via linkage, e.g., Ser-Ser, to the amino terminus of the immunogenic peptide. As another example of lipid priming of CTL responses, E. coli lipoproteins, such as tripalmitoyl-S-glycerylcysteinlyseryl-serine (P 3 CSS) can be used to prime virus specific CTL when covalently attached to an appropriate peptide. See, Deres et al., Nature 342:561-564 (1989), incorporated herein by reference. Peptides of the invention can be coupled to P 3 CSS, for example, and the lipopeptide administered to an individual to specifically prime a CTL response to the target antigen. Further, as the induction of neutralizing antibodies can also be primed with P 3 CSS conjugated to a peptide which displays an appropriate epitope, the two compositions can be combined to more effectively elicit both humoral and cell-mediated responses to infection. In addition, additional amino acids can be added to the termini of a peptide to provide for ease of linking peptides one to another, for coupling to a carrier support, or larger peptide, for modifying the physical or chemical properties of the peptide or oligopeptide, or the like. Amino acids such as tyrosine, cysteine, lysine, glutamic or aspartic acid, or the like, can be introduced at the C- or N-terminus of the peptide or oligopeptide. Modification at the C terminus in some cases may alter binding characteristics of the peptide. In addition, the peptide or oligopeptide sequences can differ from the natural sequence by being modified by terminal-NH 2 acylation, e.g., by alkanoyl (C1-C20) or thioglycolyl acetylation, terminal-carboxyl amidation, e.g., ammonia, methylamine, etc. In some instances these modifications may provide sites for linking to a support or other molecule. The peptides of the invention can be prepared in a wide variety of ways. Because of their relatively short size, the peptides can be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols. See, for example, Stewart and Young, Solid Phase Peptide Synthesis. 2d. ed., Pierce Chemical Co. (1984), supra. Alternatively, recombinant DNA technology may be employed wherein a nucleotide sequence which encodes an immunogenic peptide of interest is inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression. These procedures are generally known in the art, as described generally in Sambrook et al., Molecular Cloning. A Laboratory Manual. I 8 Cold Spring Harbor Press, Cold Spring Harbor, New York (1982), which is incorporated herein by reference. Thus, fusion proteins which comprise one or more peptide sequences of the invention can be used to present the appropriate T cell epitope. As the coding sequence for peptides of the length contemplated herein can be synthesized by chemical techniques, for example, the phosphotriester method of Matteucci et al., J. Am. Chem. Soc. 103:3185 (1981), modification can be made simply by substituting the appropriate base(s) for those encoding the native peptide sequence. The coding sequence can then be provided with appropriate linkers and ligated into expression vectors commonly available in the art, and the vectors used to transform suitable hosts to produce the desired fusion protein. A number of such vectors and suitable host systems are now available. For expression of the fusion proteins, the coding sequence will be provided with operably linked start and stop codons, promoter and terminator regions and usually a replication system to provide an expression vector for expression in the desired cellular host. For example, promoter sequences compatible with bacterial hosts are provided in plasmids containing convenient restriction sites for insertion of the desired coding sequence. The resulting expression vectors are transformed into suitable bacterial hosts. Of course, yeast or mammalian cell hosts may also be used, employing suitable vectors and control sequences. The peptides of the present invention and pharmaceutical and vaccine compositions thereof are useful for administration to mammals, particularly humans, to treat and/or prevent viral infection and cancer. Examples of diseases which can be treated using the immunogenic peptides of the invention include prostate cancer, hepatitis B, hepatitis C, ALDS, renal carcinoma, cervical carcinoma, lymphoma, CMV and condlyloma acuminatum. For pharmaceutical compositions, the immunogenic peptides of the invention are administered to an individual already suffering from cancer or infected with the virus of interest. Those in the incubation phase or the acute phase of infection can be treated with the immunogenic peptides separately or in conjunction with other treatments, as appropriate. In therapeutic applications, compositions are administered to a patient in an amount sufficient to elicit an effective CTL response to the virus or tumor antigen and to cure or at least partially arrest symptoms and/or complications. An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on, e.g., the peptide composition, the manner of administration, the stage and severity of the disease being treated, the weight and general state of health of the patient, and the judgment of the prescribing physician, but generally range for the initial immunization (that is for therapeutic or prophylactic administration) from about 1.0 μg to about 5000 μg of peptide for a 70 kg patient, followed by boosting dosages of from about 1.0 μg to about 1000 μg of peptide pursuant to a boosting regimen over weeks to months depending upon the patient's response and condition by measuring specific CTL activity in the patient's blood. It must be kept in mind that the peptides and compositions of the present invention may generally be employed in serious disease states, that is, life- threatening or potentially life threatening situations. In such cases, in view of the minimization of extraneous substances and the relative nontoxic nature of the peptides, it is possible and may be felt desirable by the treating physician to administer substantial excesses of these peptide compositions. For therapeutic use, administration should begin at the first sign of viral infection or the detection or surgical removal of tumors or shortly after diagnosis in the case of acute infection. This is followed by boosting doses until at least symptoms are substantially abated and for a period thereafter. In chronic infection, loading doses followed by boosting doses may be required. Treatment of an infected individual with the compositions of the invention may hasten resolution of the infection in acutely infected individuals. For those individuals susceptible (or predisposed) to developing chronic infection the compositions are particularly useful in methods for preventing the evolution from acute to chronic infection. Where the susceptible individuals are identified prior to or during infection, for instance, as described herein, the composition can be targeted to them, minimizing need for administration to a larger population. The peptide compositions can also be used for the treatment of chronic infection and to stimulate the immune system to eliminate virus-infected cells in carriers. It is important to provide an amount of immuno-potentiating peptide in a formulation and mode of administration sufficient to effectively stimulate a cytotoxic T cell response. Thus, for treatment of chronic infection, a representative dose is in the range of about 1.0 μg to about 5000 μg, preferably about 5 μg to 1000 μg for a 70 kg patient per dose. Immunizing doses followed by boosting doses at established intervals, e.g., from one to four weeks, may be required, possibly for a prolonged period of time to effectively immunize an individual. In the case of chronic infection, administration should continue until at least clinical symptoms or laboratory tests indicate that the viral infection has been eliminated or substantially abated and for a period thereafter. The pharmaceutical compositions for therapeutic treatment are intended for parenteral, topical, oral or local administration. Preferably, the pharmaceutical compositions are administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. Thus, the invention provides compositions for parenteral administration which comprise a solution of the immunogenic peptides dissolved or suspended in an acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers may be used, e.g., water, buffered water, 0.8% saline, 0.3% glycine, hyaluronic acid and the like. These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc. The concentration of CTL stimulatory peptides of the invention in the pharmaceutical formulations can vary widely, i.e., from less than about 0.1%, usually at or at least about 2% to as much as 20% to 50% or more by weight, and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected. The peptides of the invention may also be administered via liposomes, which serve to target the peptides to a particular tissue, such as lymphoid tissue, or targeted selectively to infected cells, as well as increase the half-life of the peptide composition. Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. In these preparations the peptide to be delivered is incorporated as part of a liposome, alone or in conjunction with a molecule which binds to, e.g., a receptor prevalent among lymphoid cells, such as monoclonal antibodies which bind to the CD45 antigen, or with other therapeutic or immunogenic compositions. Thus, liposomes either filled or decorated with a desired peptide of the invention can be directed to the site of lymphoid cells, where 4655 21 the liposomes then deliver the selected therapeutic/immunogenic peptide compositions. Liposomes for use in the invention are formed from standard vesicle-forming lipids, which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration ' of, e.g., liposome size, acid lability and stability of the liposomes in the blood stream. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka et al., Ann. Rev. Bioohvs. Bioeng. 9:467 (1980), U.S. Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, incorporated herein by reference. For targeting to the immune cells, a ligand to be incorporated into the liposome can include, e.g., antibodies or fragments thereof specific for cell surface determinants of the desired immune system cells. A liposome suspension containing a peptide may be administered intravenously, locally, topically, etc. in a dose which varies according to, inter alia, the manner of administration, the peptide being delivered, and the stage of the disease being treated. For solid compositions, conventional nontoxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable nontoxic composition is formed by incorporating any of the normally employed excipients, such as those carriers previously listed, and generally 10-95% of active ingredient, that is, one or more peptides of the invention, and more preferably at a concentration of 25%-75%. For aerosol administration, the immunogenic peptides are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of peptides are 0.01%-20% by weight, preferably 1%-10% The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%. The balance of the composition is ordinarily propellant. A carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery. In another aspect the present invention is directed to vaccines which contain as an active ingredient an immunogenically effective amount of an immunogenic peptide as described herein. The peptide(s) may be introduced into a host, including humans, linked to its own carrier or as a homopolymer or heteropolymer of active peptide units. Such a polymer has the advantage of increased immunological reaction and, where different peptides are used to make up the polymer, the additional ability to induce antibodies and/or CTLs that react with different antigenic determinants of the virus or tumor cells. Useful carriers are well known in the art, and include, e.g., thyroglobulin, albumins such as human serum albumin, tetanus toxoid, polyamino acids such as poly(lysi e:glutamic acid), influenza, hepatitis B virus core protein, hepatitis B virus recombinant vaccine and the like. The vaccines can also contain a physiologically tolerable (acceptable) diluent such as water, phosphate buffered saline, or saline, and further typically include an adjuvant. Adjuvants such as incomplete Freund's adjuvant, aluminum phosphate, aluminum hydroxide, or alum are materials well known in the art. And, as mentioned above, CTL responses can be primed by conjugating peptides of the invention to lipids, such as P3CSS. Upon immunization with a peptide composition as described herein, via injection, aerosol, oral, transdermal or other route, the immune system of the host responds to the vaccine by producing large amounts of CTLs specific for the desired antigen, and the host becomes at least partially immune to later infection, or resistant to developing chronic infection. Vaccine compositions containing the peptides of the invention are administered to a patient susceptible to or otherwise at risk of viral infection or cancer to elicit an immune response against the antigen and thus enhance the patient's own immune response capabilities. Such an amount is defined to be an "immunogenically effective dose." In this use, the precise amounts again depend on the patient's state of health and weight, the mode of administration, the nature of the formulation, etc., but generally range from about 1.0 μg to about 5000 μg per 70 kilogram patient, more commonly from about 10 μg to about 500 μg mg per 70 kg of body weight. In some instances it may be desirable to combine the peptide vaccines of the invention with vaccines which induce neutralizing antibody responses to the virus of interest, particularly to viral envelope antigens. For therapeutic or immunization purposes, nucleic acids encoding one or more of the peptides of the invention can also be administered to the patient. A number of methods are conveniently used to deliver the nucleic acids to the patient. For instance, the nulceic acid can be delivered directly, as "naked DNA". This approach is described, for instance, in Wolff et. al, Science 247: 1465-1468 (1990) as well as U.S. Patent Nos. 5,580,859 and 5,589,466. The nucleic acids can also be administered using ballistic delivery as described, for instance, in U.S. Patent No. 5,204,253. Particles comprised solely of DNA can be administered. Alternatively, DNA can be adhered to particles, such as gold particles. The nucleic acids can also be delivered complexed to cationic compounds, such as cationic lipids. Lipid-mediated gene delivery methods are described, for instance, in WO 96/18372; WO 93/24640; Mannino and Gould-Fogerite (1988) BioTechniques 6(7): 682-691; Rose U.S. Pat No. 5,279,833; WO 91/06309; and Feigner et al. (1987) Proc. Natl. Acad. Sci. USA 84: 7413-7414. The peptides of the invention can also be expressed by attenuated viral hosts, such as vaccinia or fowlpox. This approach involves the use of vaccinia virus as a vector to express nucleotide sequences that encode the peptides of the invention. Upon introduction into an acutely or chronically infected host or into a noninfected host, the recombinant vaccinia virus expresses the immunogenic peptide, and thereby elicits a host CTL response. Vaccinia vectors and methods useful in immunization protocols are described in, e.g.,U.S. Patent No. 4,722,848, incorporated herein by reference. Another vector is BCG (Bacille Calmette Guerin). BCG vectors are described in Stover et al. (Nature 351:456-460 (1991)) which is incorporated herein by reference. A wide variety of other vectors useful for therapeutic administration or immunization of the peptides of the invention, e.g., Salmonella typhi vectors and the like, will be apparent to those skilled in the art from the description herein. A preferred means of administering nucleic acids encoding the peptides of the invention uses minigene constructs encoding multiple epitopes of the invention. To create a DNA sequence encoding the selected CTL epitopes (minigene) for expression in human cells, the amino acid sequences of the epitopes are reverse translated. A human codon usage table is used to guide the codon choice for each amino acid. These epitope- encoding DNA sequences are directly adjoined, creating a continuous polypeptide sequence. To optimize expression and/or immunogenicity, additional elements can be incorporated into the minigene design. Examples of amino acid sequence that could be reverse translated and included in the minigene sequence include: helper T lymphocyte epitopes, a leader (signal) sequence, and an endoplasmic reticulum retention signal. In addition, MHC presentation of CTL epitopes may be improved by including synthetic (e.g. poly-alanine) or naturally-occurring flanking sequences adjacent to the CTL epitopes. The minigene sequence is converted to DNA by assembling oligonucleotides that encode the plus and minus strands of the minigene. Overlapping oligonucleotides (30-100 bases long) are synthesized, phosphorylated, purified and annealed under appropriate conditions using well known techniques, he ends of the oligonucleotides are joined using T4 DNA ligase. This synthetic minigene, encoding the CTL epitope polypeptide, can then cloned into a desired expression vector. Standard regulatory sequences well known to those of skill in the art are included in the vector to ensure expression in the target cells. Several vector elements are required: a promoter with a down-stream cloning site for minigene insertion; a polyadenylation signal for efficient transcription termination; an E. coli origin of replication; and an E. coli selectable marker (e.g. ampicillin or kanamycin resistance). Numerous promoters can be used for this purpose, e.g., the human cytomegalovirus (hCMV) promoter. See, U.S. Patent Nos. 5,580,859 and 5,589,466 for other suitable promoter sequences. Additional vector modifications may be desired to optimize minigene expression and immunogenicity. In some cases, introns are required for efficient gene expression, and one or more synthetic or naturally-occurring introns could be incorporated into the transcribed region of the minigene. The inclusion of mRNA stabilization sequences can also be considered for increasing minigene expression. It has recently been proposed that immunostimulatory sequences (ISSs or CpGs) play a role in the immunogenicity of DNA vaccines. These sequences could be included in the vector, outside the minigene coding sequence, if found to enhance immunogenicity. In some embodiments, a bioistronic expression vector, to allow production of the minigene-encoded epitopes and a second protein included to enhance or decrease immunogenicity can be used. Examples of proteins or polypeptides that could beneficially enhance the immune response if co-expressed include cytokines (e.g., TL2, IL12, GM-CSF), cytokine-inducing molecules (e.g. LeLF) or costimulatory molecules. Helper (HTL) epitopes could be joined to intracellular targeting signals and expressed separately from the CTL epitopes. This would allow direction of the HTL epitopes to a cell compartment different than the CTL epitopes. If required, this could facilitate more efficient entry of HTL epitopes into the MHC class II pathway, thereby improving CTL induction. In contrast to CTL induction, specifically decreasing the immune response by co-expression of immunosuppressive molecules (e.g. TGF-β) may be beneficial in certain diseases. Once an expression vector is selected, the minigene is cloned into the polylinker region downstream of the promoter. This plasmid is transformed into an appropriate E. coli strain, and DNA is prepared using standard techniques. The orientation and DNA sequence of the minigene, as well as all other elements included in the vector, are confirmed using restriction mapping and DNA sequence analysis. Bacterial cells harboring the correct plasmid can be stored as a master cell bank and a working cell bank. Therapeutic quantities of plasmid DNA are produced by fermentation in E. coli, followed by purification. Aliquots from the working cell bank are used to inoculate fermentation medium (such as Terrific Broth), and grown to saturation in shaker flasks or a bioreactor according to well known techniques. Plasmid DNA can be purified using standard bioseparation technologies such as solid phase anion-exchange resins supplied by Quiagen. If required, supercoiled DNA can be isolated from the open circular and linear forms using gel electrophoresis or other methods. Purified plasmid DNA can be prepared for injection using a variety of formulations. The simplest of these is reconstitution of lyophilized DNA in sterile phosphate-buffer saline (PBS). A variety of methods have been described, and new techniques may become available. As noted above, nucleic acids are conveniently formulated with cationic lipids. In addition, glycolipids, fusogenic liposomes, peptides and compounds referred to collectively as protective, interactive, non-condensing (PLNC) could also be complexed to purified plasmid DNA to influence variables such as stability, intramuscular dispersion, or trafficking to specific organs or cell types. Target cell sensitization can be used as a functional assay for expression and MHC class I presentation of minigene-encoded CTL epitopes. The plasmid DNA is introduced into a mammalian cell line that is suitable as a target for standard CTL chromium release assays. The transfection method used will be dependent on the final formulation. Electroporation can be used for "naked" DNA, whereas cationic lipids allow direct in vitro transfection. A plasmid expressing green fluorescent protein (GFP) can be co-transfected to allow enrichment of transfected cells using fluorescence activated cell sorting (FACS). These cells are then chromium-51 labeled and used as' target cells for epitope-specific CTL lines. Cytolysis, detected by 51Cr release, indicates production of MHC presentation of minigene-encoded CTL epitopes. In vivo immunogenicity is a second approach for functional testing of minigene DNA formulations. Transgenic mice expressing appropriate human MHC molecules are immunized with the DNA product. The dose and route of administration are formulation dependent (e.g. IM for DNA in PBS, LP for lipid-complexed DNA). Twenty-one days after immunization, splenocytes are harvested and restimulated for 1 week in the presence of peptides encoding each epitope being tested. These effector cells (CTLs) are assayed for cytolysis of peptide-loaded, chromium-51 labeled target cells using standard techniques. Lysis of target cells sensitized by MHC loading of peptides corresponding to minigene-encoded epitopes demonstrates DNA vaccine function for in vivo induction of CTLs. Antigenic peptides may be used to elicit CTL ex vivo, as well. The resulting CTL, can be used to treat chronic infections (viral or bacterial) or tumors in patients that do not respond to other conventional forms of therapy, or will not respond to a peptide vaccine approach of therapy. Ex vivo CTL responses to a particular pathogen (infectious agent or tumor antigen) are induced by incubating in tissue culture the patient's CTL precursor cells (CTLp) together with a source of antigen-presenting cells (APC) and the appropriate immunogenic peptide. After an appropriate incubation time (typically 1-4 weeks), in which the CTLp are activated and mature and expand into effector CTL, the cells are infused back into the patient, where they will destroy their specific target cell (an infected cell or a tumor cell). The peptides may also find use as diagnostic reagents. For example, a peptide of the invention may be used to determine the susceptibility of a particular individual to a treatment regimen which employs the peptide or related peptides, and thus may be helpful in modifying an existing treatment protocol or in determining a prognosis for an affected individual. In addition, the peptides may also be used to predict which individuals will be at substantial risk for developing chronic infection. The following example is offered by way of illustration, not by way of limitation. EXAMPLE 1 Class I antigen isolation was carried out as described in the related applications, noted above. Naturally processed peptides were then isolated and sequenced as described there. An allele-specific motif and algorithms were determined and quantitative binding assays were carried out. Using the motifs identified above for the HLA-A2.1 allele amino acid sequences from a number of antigens were analyzed for the presence of these motifs. Table 3 provides the results of these searches. The letter "J" represents norleucine. The above examples are provided to illustrate the invention but not to limit its scope. Other variants of the invention will be readily apparent to one of ordinary skill in the art and are encompassed by the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference. Table 3 Peptide AA Sequence Source A*0201 17.0317 9 LQIGNIISI Flu.24 0.0130 38.0103 9 NLSLSCHAA CEA.432 0.0110 1233.11 9 YLSGANLNV CEA.605V9 0.0690 1295.03 9 SMPPPGTRV p53.149M2 0.0290 1295.04 9 SLPPPGTRV p53.149L2 0.0410 1317.24 9 KTCPVQLWV p53.139 0.0069 1323.02 9 KLLPENNVV p53.24V9 0.0130 1323.04 9 ALNKMFBQV p53.129B7V9 0.0260 1323.06 9 KLBPVQLWV p53.139L2B3 0.1100 1323.08 9 BLTIHYNYV P53.229B1L2V9 0.0430 1323.18 10 LLPPQHLΓRV p53.188L2 0.0061 1323.29 11 YMCNSSCMGGM p53.236 0.0075 1323.31 11 YLCNSSCMGGV p53.236L2Vll 0.2300 1323.34 11 KLYQGSYGFRV p53.101L2Vl l 0.0620 1324.07 9 CQLAKTCPV p53.135 0.0240 1325.01 9 RLPEAAPPV p53.65L2 0.0640 1325.02 9 GLAPPQHLV p53.187V9 0.0130 1325.04 9 KMAELVHFL MAGE3.112M2 0.2100 Peptide Sequence Source A*0201 1325.05 9 KLAELVHFL MAGE3.112L2 0.2500 1326.01 9 CLLAKTCPV p53.135L2 0.0400 1326.02 9 KLSQHMTEV p53.164L2 0.0410 1326.04 9 ELAPWAPV p53.68L2V9 0.0860 1326.06 10 QLAKTCPVQV p53.136 0.0320 1326.08 9 HLTEVVRRV p53.168L2 0.0180 1329.01 11 KTYQGSYGFRL 0.0028 1329.03 10 WVPYEPPEV p53.216 0.0081 1329.14 9 BQLAKTBPV P 53.135B1B7 0.0490 1329.15 9 BLLAKTBPV P 53.135B1L2B7 0.1100 1330.01 9 QIIGYVIGT CEA.78 0.0160 1330.02 9 QLIGYVIGV CEA.78L2V9 0.5300 1330.05 9 YVCGIQNSV CEA.569 0.0510 1330.06 9 YLCGIQNSV CEA.569L2 0.1000 1330.07 9 ATVGLMIGV CEA.687 0.1400 1330.08 9 ALVGΓMIGV CEA.687L2 0.5000 1330.09 10 VLYGPDDPTI CEA.411 0.0170 1330.10 10 VLYGPDDPTV CEA.411V10 0.0310 1331.02 9 DLMLSPDDV p53.42V9 1331.03 9 ALMLSPDDI p53.42Al 1331.04 9 ALMLSPDDV p53.42AlV9 1331.05 9 DLMLSPADI p53.42A7 1331.06 9 DLMLSPADV p53.42A7V9 1331.07 9 DLMLSPDAI p53.42A8 1331.08 9 DLMLSPDAV p53.42A8V9 38.0007 9 AILTFGSFV KSHV.89 0.0850 38.0009 9 HLRDFALAV KSHV.106 0.0183 38.0015 9 ALLGSIALL KSHV.155 0.0470 38.0018 9 ALLATILAA KSHV.161 0.0490 38.0019 9 LLATILAAV KSHV.162 0.1600 38.0022 9 RLFADELAA KSHV.14 0.0150 Peptide AA Sequence Source A*0201 38.0024 9 YLSKCTLAV KSHV.65 0.2000 38.0026 9 LVYHIYSKI KSHV.153 0.0457 38.0029 9 SMYLCILSA KSHV.208 0.0250 38.0030 9 YLCILSALV KSHV.210 0.3500 38.0033 "" 9 VMFSYLQSL KSHV.268 0.5000 38.0035 9 RLHVYAYSA KSHV.285 0.0270 38.0039 9 GLQTLGAFV KSHV.98 0.0110 38.0040 9 FVEEQMTWA KSHV.105 0.0380 38.0041 9 QMTWAQTVV KSHV.109 0.0110 38.0042 9 IILDTALFV KSHV.130 0.6800 38.0043 9 AIFVCNAFV KSHV.135 0.0910 38.0046 9 AMGNRLVEA KSHV.172 0.0200 " 38.0047 9 RLVEACNLL KSHV.176 0.0180 38.0059 9 TLSΓV FSL KSHV.198 0.2200 38.0063 9 KLSVLLLEV KSHV.292 0.1400 38.0064 9 LLLEVNRSV KSHV.296 0.0270 38.0068 9 FVSSPTLPV KSHV.78 0.0350 38.0070 9 AMLVLLAEI KSHV.281 0.0820 38.0075 9 QMARLAWEA KSHV.1116 0.0990 38.0131 10 VLAIEGIFMA KSHV.10 0.0730 38.0132 10 YLYHPLLSPI KSHV.27 0.1400 38.0134 10 SLFEAMLANV KSHV.49 0.9500 38.0135 10 STTGLNQLGL KSHV.62 0.0710 38.0137 10 LATLTFGSFV KSHV.88 0.0160 38.0139 10 ALLGSIALLA KSHV.155 0.0360 38.0141 10 ALLATLLAAV KSHV.161 0.1100 38.0142 10 LLATILAAVA KSHV.162 0.0110 38.0143 10 RLFADELAAL KSHV.14 0.1800 38.0148 10 YLSKCTLAVL KSHV.65 0.0300 38.0150 10 LLVYHIYSKI KSHV.152 0.0130 38.0151 10 SMYLCILSAL KSHV.208 0.0360 Peptide AA Sequence Source A*0201 38.0153 10 HLHRQMLSFV KSHV.68 0.0160 38.0163 10 LLCGKTGAFL KSHV.167 0.0100 38.0164 10 ETLSΓVTFSL KSHV.197 0.0180 39.0063 9 VMCTYSPPL mp53.119 1.4000 39.0065 9 KLFCQLAKT mp53.129 0.0160 39.0067 9 ATPPAGSRV mp53.146 0.0130 39.0133 10 FLQSGTAKSV mp53.110 0.0180 39.0169 10 CMDRGLTVFV KSHV.311 0.0120 39.0170 10 VLLNWWRWRL KSHV.327 0.1500 40.0070 9 GVFTGLTHI HCV.1565 0.0110 40.0072 9 QMWKCLIRL HCV.1611 0.0620 40.0074 9 LMTCMSADL HCV.1650 0.0121 40.0076 9 ALAAYCLST HCV.1674 0.2500 40.0080 9 VLSGKPAII HCV.1692 0.0150 40.0082 9 FISGIQYLA HCV.1773 * 0.1000 40.0134 10 YLMTCMSADL HCV.1649 0.0300 40.0137 10 AIASLMAFTA HCV.1791 0.0580 40.0138 10 GLAGAAIGSV HCV.1838 0.0320 41.0058 8 MIGVLVGV CEA.692 0.0120 41.0061 9 VLPLAYISL TRP1 0.0110 41.0062 9 SLGCLFFPL TRP1 0.9700 41.0063 9 PLAYISLFL TRP1 0.0220 41.0065 9 LMLFYQVWA TRP1 0.0270 41.0071 9 NISIYNYFV TRP1 0.2300 41.0072 9 NISVYNYFV TRP1 0.0600 41.0075 9 FVWTHYYSV TRP1 1.5000 41.0077 9 FLTWHRYHL TRP1 0.5500 41.0078 9 LTWHRYHLL TRP1 0.1600 41.0082 9 MLQEPSFSL TRP1 0.6900 41.0083 9 SLPYWNFAT TRP1 0.0110 41.0088 9 RLPEPQDVA TRP1 0.0180 Peptide AA Sequence Source A*0201 41.0090 9 VTQCLEVRV TRP1 0.0160 41.0096 9 LLHTFTDAV TRP1 0.2700 41.0100 9 NMVPFWPPV TRP1 0.6200 41.0104 9 AWGALLLV TRP1 0.0210 41.0105 9 AWAALLLV TRP1 0.0390 41.0108 9 LLVAAIFGV TRP1 1.9000 41.0112 9 SMDEANQPL TRP1 0.0770 41.0114 9 VLPLAYISV TRP1 0.1100 41.0115 9 SLGCIFFPV TRP1 3.2000 41.0116 9 PLAYISLFV TRP1 0.0310 41.0117 9 LLLFQQARV TRP1 0.1100 41.0118 9 LMLFYQVWV TRP1 2.4000 41.0119 9 LLPSSGPGV TRP1 0.3700 41.0121 9 NLSIYNYFV TRP1 0.9700 41.0122 9. NLSVYNYFV TRP1 0.8700 41.0123 9 FLWTHYYSV TRP1 5.6000 41.0124 9 SLKKTFLGV TRP1 0.0224 41.0125 9 FLTWHRYHV TRP1 0.3800 41.0129 9 MLQEPSFSV TRP1 1.6000 41.0130 9 SLPYWNFAV TRP1 0.5700 41.0131 9 ALGKNVCDV TRP1 0.0160 41.0132 9 SLLISPNSV TRP1 0.1300 41.0133 9 SLFSQWRW TRP1 0.0740 41.0134 9 TLGTLCNSV TRP1 0.0330 41.0136 9 RLPEPQDW TRP1 0.1000 41.0137 9 VLQCLEVRV TRP1 0.0360 41.0138 9 SLNSFRNTV TRP1 0.0140 41.0139 9 SLDSFRNTV TRP1 0.0440 41.0141 9 FLNGTGGQV TRP1 0.0220 41.0142 9 VLLHTFTDV TRP1 0.0180 41.0145 9 ALVGALLLV TRP1 0.2600 4655 32 Peptide AA Sequence Source A*0201 41.0146 9 ALVAALLLV TRPl 0.5800 41.0147 9 LLVALLFGV TRP1 1.0000 41.0148 9 YLLRARRSV TRPl 0.0170 41.0149 9 SMDEANQPV TRPl 0.1600 41.0151 10 SLGCLFFPLL . TRPl 0.1800 41.0157 10 GMCCPDLSPV TRPl 0.0950 41.0160 10 AACNQKLLTV TRPl 0.0120 41.0162 10 FLTWHRYHLL TRPl 0.0830 41.0166 10 SLHNLAHLFL TRPl 0.3900 41.0174 10 LLLVAALFGV TRPl 0.3000 41.0177 10 LLVAALFGVA TRPl 0.0820 41.0178 10 ALLFGTASYL TRPl 0.0230 41.0180 10 SMDEANQPLL TRPl 0.0250 41.0181 10 LLTDQYQCYA TRPl 0.0320 41.0183 10 SLGCIFFPLV TRPl 0.3200 41.0186 10 FLMLFYQVWV TRPl 0.8100 41.0189 10 ALCDQRVLΓV TRPl 0.0530 41.0190 10 ALCNQKILTV TRPl 0.0770 41.0191 10 FLTWHRYHLV TRPl 0.0510 41.0197 10 SLHNLAHLFV TRPl 0.5000 41.0198 10 NLAHLFLNGV TRPl 0.4100 41.0199 10 NMVPFWPPVV TRPl 0.2800 41.0201 10 ILVVAALLLV TRPl 0.0190 41.0203 10 LLVALLFGTV TRPl 0.1200 41.0205 10 ALΓFGTASYV TRPl 0.0900 41.0206 10 SMDEANQPLV TRPl 0.0350 41.0207 10 LLTDQYQCYV TRPl 0.2100 41.0212 11 LLIQNIIQNDT CEA.107 0.0140 41.0214 11 IIQNDTGFYTL CEA.112 0.0130 41.0221 11 TLFNVTRNDTA CEA.201 0.0110 41.0235 11 LTLLSVTRNDV CEA.378 0.0150 Peptide AA Sequence Source A*0201 41.0243 GLYTCQANNSA CEA.473 0.0290 41.0268 ATVGLMIGVLV CEA.687 0.0160 44.0075 GLVPPQHLΓRV mp53.184.V3 0.0370 44.0087 GLAPPVHLLRV mp53.184.V6 0.0330 44.0092 GLAPPEHLΓRV mp53.184.E6 0.1600 1227.10 9 ILIGVLVGV CEA.691.L2 0.2300 1234.26 10 YLLMVKCWMV Her2/neu.952.L2 0.3800 V10 1295.06 9 LLGRDSFEV mp53.261 0.2000 1319.01 9 FMYSDFHFI Flu.RRP2.446 0.4400 1319.06 9 NMLSTVLGV Flu.RRP2.446 0.1700 1319.14 9 SLENFRAYV Flu.RRP2.446 0.0430 1325.06 KMAELVHFV Mage3.112 0.1900 1325.07 KLAELVHFV Mage3.112 0.3500 1334.01 VLIQRNPQV Her2/neu.l53.V9 0.0910 1334.02 VLLGWFGV Her2/neu.665.L2 2.1000 V9 1334.03 SLISAVVGV Her2/neu.653.L2 0.7000= V9 1334.04 YMLMVKBWMI Her2/neu.952.B7 0.2700 1334.05 YLLMVKBWMV Her2/neu.952.L2 0.6900 B7V10 1334.06 KLWEELSVV Mage3.220.L2V 0.4500 9 1334.08 AMBRWGLLV Her2/neu.5.M2B 0.1400 3V9 1345.01 9 IHGVLVGV CEA.691J2 . 0.0570 1345.02 9 ATVGIJIGV CEA.687J6 0.1595 1345.03 9 SJPPPGTRV p53.149J2 0.0545 1345.04 10 LVFGIELJEV MAGE3.160J8 0.7650 918.12 8 ILGFVFTL Flu.Ml.59 0.7900 Peptide AA Sequence Source A*0201 1095.22 9 KLFGSLAFL Her2/neu 1090.01 10 YLQLVFGLEV MAGE2 1126.01 9 MMNDQLMFL PSM 1126.02 10 ALVLAGGFFL PSM 1126.03 9 WLCAGALVL PSM 1126.05 9 MVFELANSI PSM 1126.06 10 RMMNDQLMFL PSM 1126.09 9 LVLAGGFFL PSM 1126.10 9 VLAGGFFLL PSM 1126.12 9 LLHETDSAV PSM 1126.14 9 LMYSLVHNL PSM 1126.16 10 QLMFLERAFI PSM 1126.17 9 LMFLERAFI PSM 1126.20 10 KLGSGNDFEV PSM 1129.01 10 LLQERGVAYI PSM 1129.04 10 GMPEGDLVYV PSM 1129.05 10 FLDELKAENI PSM 1129.08 9 ALFDIESKV PSM 1129.10 10 GLPSIPVHPI PSM II. Non-HLA-A2 Motifs The present invention also relates to the determination of allele-specific peptide motifs for human Class I MHC (sometimes referred to as HLA) allele subtypes. These motifs are then used to define T cell epitopes from any desired antigen, particularly those associated with human viral diseases, cancers or autoimmune diseases, for which the amino acid sequence of the potential antigen or autoantigen targets is known. Epitopes on a number of potential target proteins can be identified in this manner. Examples of suitable antigens include prostate specific antigen (PSA), hepatitis B core and surface antigens (HBVc, HBVs) hepatitis C antigens, Epstein-Barr virus antigens, melanoma antigens (e.g., MAGE-1), human immunodeficiency virus (HIV) antigens and human papilloma virus (HPV) antigens, Lassa virus, mycobacterium tuberculosis (MT), p53, CEA, and Her2/neu. Peptides comprising the epitopes from these antigens are synthesized and then tested for their ability to bind to the appropriate MHC molecules in assays using, for example, purified class I molecules and radioiodonated peptides and/or cells expressing empty class I molecules by, for instance, immunofluorescent staining and flow microfluorimetry, peptide-dependent class I assembly assays, and inhibition of CTL recognition by peptide competition. Those peptides that bind to the class I molecule are further evaluated for their ability to serve as targets for CTLs derived from infected or immunized individuals, as well as for their capacity to induce primary in vitro or in vivo CTL responses that can give rise to CTL populations capable of reacting with virally infected target cells or tumor cells as potential therapeutic agents. The MHC class I antigens are encoded by the HLA-A, B, and C loci. HLA-A and B antigens are expressed at the cell surface at approximately equal densities, whereas the expression of HLA-C is significantly lower (perhaps as much as 10-fold lower). Each of these loci have a number of alleles. The peptide binding motifs of the invention are relatively specific for each allelic subtype. For peptide-based vaccines, the peptides of the present invention preferably comprise a motif recognized by an MHC I molecule having a wide distribution in the human population. Since the MHC alleles occur at different frequencies within different ethnic groups and races, the choice of target MHC allele may depend upon the target population. Table 4 shows the frequency of various alleles at the HLA-A locus products among different races. For instance, the majority of the Caucasoid population can be covered by peptides which bind to four HLA-A allele subtypes, specifically HLA- A2.1, Al, A3.2, and A24.1. Similarly, the majority of the Asian population is encompassed with the addition of peptides binding to a fifth allele HLA-Al 1.2. TABLE 4 A Allele/Subtvpe N(69 * A(54) CC502 Al 10.1(7) 1.8(1) 27.4(138) A2.1 11.5(8) 37.0(20) 39.8(199) A2.2 10.1(7) 0 3.3(17) 4655 36 A2.3 1-4(1) 5.5(3) 0.8(4) ' , A2.4 - - - A2.5 - - - A3.1 1.4(1) 0 0.2(0) A3.2 5.7(4) 5.5(3) 21.5(108) All.l 0 5.5(3) 0 A11.2 . 5.7(4) 31.4(17) 8.7(44) A11.3 0 3.7(2) 0 A23 4.3(3) - 3.9(20) A24 2.9(2) 27.7(15) 15.3(77) A24.2 - - - A24.3 - - - A25 1.4(1) - 6.9(35) A26.1 4.3(3) 9.2(5) 5.9(30) A26.2 7.2(5) - 1.0(5) A26V - 3.7(2) - A28.1 10.1(7) - 1.6(8) A28.2 1.4(1) - 7.5(38) A29.1 1.4(1) - 1.4(7) A29.2 10.1(7) 1.8(1) 5.3(27) A30.1 8.6(6) - 4.9(25) A30.2 1.4(1) - 0.2(1) A30.3 7.2(5) - 3.9(20) A31 4.3(3) 7.4(4) 6.9(35) A32 2.8(2) - 7.1(36) Aw33.1 8.6(6) - 2.5(13) Aw33.2 2.8(2) 16.6(9) 1.2(6) Aw34.1 1.4(1) - - Aw34.2 14.5(10) - 0.8(4) Aw36 5.9(4) - - Table compiled from B. DuPont, Immunobiology of HLA, Vol. I, Histo compatibility Testing 1987, Springer-Verlag, New York 1989. * N - negroid; A = Asian; C = Caucasoid. Numbers in parenthesis represent the number of individuals included in the analysis. The nomenclature used to describe peptide compounds follows the conventional practice wherein the amino group is presented to the left (the N-terminus) and the carboxyl group to the right (the C-terminus) of each amino acid residue. In the formulae representing selected specific embodiments of the present invention, the amino- and carboxyl-terminal groups, although not specifically shown, are in the form they would assume at physiologic pH values, unless otherwise specified. In the amino acid structure formulae, each residue is generally represented by standard three letter or single letter designations. The L-form of an amino acid residue is represented by a capital single letter or a capital first letter of a three-letter symbol, and the D-form for those amino acids is represented by a lower case single letter or a lower case three letter symbol. Glycine has no asymmetric carbon atom and is simply referred to as "Gly" or G. The procedures used to identify peptides of the present invention generally follow the methods disclosed in Falk et al., Nature 351:290 (1991), which is incorporated herein by reference. Briefly, the methods involve large-scale isolation of MHC class I molecules, typically by immunoprecipitation or affinity chromatography, from the appropriate cell or cell line. Examples of other methods for isolation of the desired MHC molecule equally well known to the artisan include ion exchange chromatography, lectin chromatography, size exclusion, high performance ligand chromatography, and a combination of all of the above techniques. A large number of cells with defined MHC molecules, particularly MHC Class I molecules, are known and readily available. For example, human EBV- transformed B cell lines have been shown to be excellent sources for the preparative isolation of class I and class II MHC molecules. Well-characterized cell lines are available from private and commercial sources, such as American Type Culture Collection ("Catalogue of Cell Lines and Hybridomas," 6th edition (1988) Rockville, Maryland, U.S.A.); National Institute of General Medical Sciences 1990/1991 Catalog of Cell Lines (NIGMS) Human Genetic Mutant Cell Repository, Camden, NJ; and ASHI Repository, Bingham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Table 5 lists some B cell lines suitable for use as sources for HLA-A alleles. All of these cell lines can be grown in large batches and are therefore useful for large scale production of MHC molecules. One of skill will recognize that these are merely exemplary cell lines and that many other cell sources can be employed. Similar EBV.B cell lines homozygous for HLA-B and HLA-C could serve as sources for HLA-B and HLA-C alleles, respectively. TABLE 5 HUMAN CELL LINES (HLA-A SOURCES) HLA-A allele B cell line Al ■ MAT COX (9022) STELNLLN (9087) A2.1 JY A3.2 EHM (9080) HO301 (9055)GM3107 A24.1 T3(9107),TISI (9042) All BVR (GM6828A) WT100 (GM8602)WT52 (GM8603) In the typical case, immunoprecipitation is used to isolate the desired allele. A number of protocols can be used, depending upon the specificity of the antibodies used. For example, allele-specific mAb reagents can be used for the affinity purification of the HLA-A, HLA-B, and HLA-C molecules. Several mAb reagents for the isolation of HLA-A molecules are available (Table 6). Thus, for each of the targeted HLA-A alleles, reagents are available that may be used for the direct isolation of the HLA-A molecules. Affinity columns prepared with these mAbs using standard techniques are successfully used to purify the respective HLA-A allele products. In addition to allele-specific mAbs, broadly reactive anti-HLA-A, B, C mAbs, such as W6/32 and B9.12.1, and one anti-HLA-B, C mAb, Bl.23.2, could be used in alternative affinity purification protocols as described in the example section below. TABLE 6 ANTIBODY REAGENTS anti-HLA Name HLA-A1 HLA-A3 GAP A3 (ATCC, HB122) HLA-11,24.1 A11.1M (ATCC, HB164) HLA-A,B,C W6/32 (ATCC, HB95) monomorphic B9.12.1 (LNSERM-CNRS) HLA-B,C B.l.23.2 (LNSERM-CNRS) monomorphic The peptides bound to the peptide binding groove of the isolated MHC molecules are eluted typically using acid treatment. Peptides can also be dissociated from class I molecules by a variety of standard denaturing means, such as heat, pH, detergents, salts, chaotropic agents, or a combination thereof. Peptide fractions are further separated from the MHC molecules by reversed-phase high performance liquid chromatography (HPLC) and sequenced. Peptides can be separated by a variety of other standard means well known to the artisan, including filtration, ultrafiltration, electrophoresis, size chromatography, precipitation with specific antibodies, ion exchange chromatography, isoelectrofocusing, and the like. Sequencing of the isolated peptides can be performed according to standard techniques such as Edman degradation (Hunkapiller, M.W., et al.. Methods Enzymol. 91, 399 [1983]). Other methods suitable for sequencing include mass spectrometry sequencing of individual peptides as previously described (Hunt, et al, Science 225:1261 (1992), which is incorporated herein by reference). Amino acid sequencing of bulk heterogenous peptides (e^, pooled HPLC fractions) from different class I molecules typically reveals a characteristic sequence motif for each class I allele. Definition of motifs specific for different class I alleles allows the identification of potential peptide epitopes from an antigenic protein whose amino acid sequence is known. Typically, identification of potential peptide epitopes is initially P T/US00/04655 40 carried out using a computer to scan the amino acid sequence of a desired antigen for the presence of motifs. The epitopic sequences are then synthesized. The capacity to bind MHC Class molecules is measured in a variety of different ways. One means is a Class I molecule binding assay as described in the related applications, noted above. Other alternatives described in the literature include inhibition of antigen presentation (Sette, et al., J. Immunol. 141:3893 (1991), in vitro assembly assays (Townsend, et al., Cell 62:285 (1990), and FACS based assays using mutated ells, such as RMA.S (Melief, et al, Eur. J. Immunol. 21:2963 (1991)). Next, peptides that test positive in the MHC class I binding assay are assayed for the ability of the peptides to induce specific CTL responses in vitro. For instance, Antigen-presenting cells that have been incubated with a peptide can be assayed for the ability to induce CTL responses in responder cell populations. Antigen-presenting cells can be normal cells such as peripheral blood mononuclear cells or dendritic cells ' (Inaba, et al, J. Exp. Med. 166:182 (1987); Boog, Eur. J. Immunol. 18:219 [1988]). Alternatively, mutant mammalian cell lines that are deficient in their ability to load class I molecules with internally processed peptides, such as the mouse cell lines RMA-S (Karre, et al.. Nature. 319:675 (1986); Ljunggren, et al, Eur. J. Immunol. 21:2963-2970 (1991)), and the human somatic T cell hybrid, T-2 (Cerundolo, et al., Nature 345:449-452 (1990)) and which have been transfected with the appropriate human class I genes are conveniently used, when peptide is added to them, to test for the capacity of the peptide to induce in vitro primary CTL responses. Other eukaryotic cell lines which could be used include various insect cell lines such as mosquito larvae (ATCC cell lines CCL 125, 126, 1660, 1591, 6585, 6586), silkworm (ATTC CRL 8851), armyworm (ATCC CRL 1711), moth (ATCC CCL 80) and Drosophila cell lines such as a Schneider cell line (see Schneider J. Embrvol. EXΌ. Morphol. 27:353-365 [1927]). Peripheral blood lymphocytes are conveniently isolated following simple venipuncture or leukapheresis of normal donors or patients and used as the responder cell sources of CTL precursors. In one embodiment, the appropriate antigen-presenting cells are incubated with 10-100 μM of peptide in serum-free media for 4 hours under appropriate culture conditions. The peptide-loaded antigen-presenting cells are then incubated with the responder cell populations in vitro for 7 to 10 days under optimized culture conditions. Positive CTL activation can be determined by assaying the cultures for the presence of CTLs that kill radiolabeled target cells, both specific peptide-pulsed P T/US00/04655 41 targets as well as target cells expressing endogenously processed foπri of the relevant virus or tumor antigen from which the peptide sequence was derived. Specificity and MHC restriction of the CTL is determined by testing against different peptide target cells expressing appropriate or inappropriate human MHC class I. The peptides that test positive in the MHC binding assays and give rise to specific CTL responses are referred to herein as immunogenic peptides. The immunogenic peptides can be prepared synthetically, or by recombinant DNA technology or from natural sources such as whole viruses or tumors. Although the peptide will preferably be substantially free of other naturally occurring host cell proteins and fragments thereof, in some embodiments the peptides can be synthetically conjugated to native fragments or particles. The polypeptides or peptides can be a variety of lengths, either in their neutral (uncharged) forms or in forms which are salts, and either free of modifications such as glycosylation, side chain oxidation, or phosphorylation or containing these modifications, subject to the condition that the modification not destroy the biological activity of the polypeptides as herein described. Desirably, the peptide will be as small as possible while still maintaining substantially all of the biological activity of the large peptide. When possible, it may be desirable to optimize peptides of the invention to a length of 9 or 10 amino acid residues, commensurate in size with endogenously processed viral peptides or tumor cell peptides that are bound to MHC class I molecules on the cell surface. Peptides having the desired activity may be modified as necessary to provide certain desired attributes, e.g., improved pharmacological characteristics, while increasing or at least retaining substantially all of the biological activity of the unmodified peptide to bind the desired MHC molecule and activate the appropriate T cell. For instance, the peptides may be subject to various changes, such as substitutions, either conservative or non-conservative, where such changes might provide for certain advantages in their use, such as improved MHC binding. By conservative substitutions is meant replacing an amino acid residue with another which is biologically and/or chemically similar, e.g., one hydrophobic residue for another, or one polar residue for another. The substitutions include combinations such as Gly, Ala; Val, He, Leu, Met; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr. The effect of single amino acid substitutions may also be probed using D-amino acids. Such modifications may be made using well known peptide synthesis procedures, as described in e.g., Merrifield, Science 232:341-347 (1986), Barany and Merrifield, The Peptides, Gross, and Meienhofer, eds. (N.Y., Academic Press), pp. 1-284 (1979); and Stewart and Young, Solid Phase Pentide ' Synthesis, (Rockford, 111., Pierce), 2d Ed. (1984), incorporated by reference herein. The peptides can also be modified by extending or decreasing the compound's amino acid sequence, e.g., by the addition or deletion of amino acids. The peptides or analogs of the invention can also be modified by altering the order or composition of certain residues, it being readily appreciated that certain amino acid residues essential for biological activity, e.g., those at critical contact sites or conserved residues, may generally not be altered without an adverse effect on biological activity. The non-critical amino acids need not be limited to those naturally occurring in proteins, such as L-α-amino acids, or their D-isomers, but may include non-natural amino acids as well, such as β-γ-δ-amino acids, as well as many derivatives of L-α-amino acids. Typically, a series of peptides with single amino acid substitutions are employed to determine the effect of electrostatic charge, hydrophobicity, etc. on binding. For instance, a series of positively charged (e.g., Lys or Arg) or negatively charged (e.g., Glu) amino acid substitutions are made along the length of the peptide revealing different patterns of sensitivity towards various MHC molecules and T cell receptors. In addition, multiple substitutions using small, relatively neutral moieties such as Ala, Gly, Pro, or ; similar residues may be employed. The substitutions may be homo-oligomers or hetero- oligomers. The number and types of residues which are substituted or added depend on the spacing necessary between essential contact points and certain functional attributes which are sought (e.g., hydrophobicity versus hydrophilicity). Increased binding affinity for an MHC molecule or T cell receptor may also be achieved by such substitutions, compared to the affinity of the parent peptide. In any event, such substitutions should employ amino acid residues or other molecular fragments chosen to avoid, for example, steric and charge interference which might disrupt binding. Amino acid substitutions are typically of single residues. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final peptide. Substitutional variants are those in which at least one residue of a peptide has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with the following Table 2 when it is desired to finely modulate the characteristics of the peptide. 00 04655 43 TABLE 2 Original Residue Exemplary Substitution Ala Ser Arg Lys, His Asn Gin Asp Glu Cys Ser Glu Asp Gly Pro His Lys; Arg He Leu; Val Leu He; Val Lys Arg; His Met Leu; He Phe Tyr; Trp Ser Thr Thr Ser Trp Tyr; Phe Tyr Trp; Phe Val He; Leu Pro Gly Substantial changes in function (e.g., affinity for MHC molecules or T cell receptors) are made by selecting substitutions that are less conservative than those in Table 2, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site or (c) " the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in peptide properties will be those in which (a) hydrophilic residue, e.g. seryl, is substituted for (or by) a hydrophobic residue, e.g. leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a residue having an electropositive side chain, e.g., lysl, arginyl, or histidyl, is substituted for (or by) an electronegative residue, e.g. glutamyl or aspartyl; or (c) a residue having a bulky side chain, e.g. phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine. , The peptides may also comprise isosteres of two or more residues in the immunogenic peptide. An isostere as defined here is a sequence of two or more residues that can be substituted for a second sequence because the steric conformation of the first sequence fits a binding site specific for the second sequence. The term specifically includes peptide backbone modifications well known to those skilled in the art. Such modifications include modifications of the amide nitrogen, the α-carbon, amide carbonyl, complete replacement of the amide bond, extensions, deletions or backbone crosslinks. See, generally, Spatola, Chemistry and Biochemistry of Amino Acids, peptides and Proteins, Vol. VII (Weinstein ed., 1983). Modifications of peptides with various amino acid mimetics or unnatural amino acids are particularly useful in increasing the stability of the peptide in vivo. Stability can be assayed in a number of ways. For instance, peptidases and various biological media, such as human plasma and serum, have been used to test stability. See, e.g., Verhoef et al, Eur. J. Drug Metab. Pharmacokin. 11:291-302 (1986). Half life of the peptides of the present invention is conveniently determined using a 25% human serum (v/v) assay. The protocol is generally as follows. Pooled human serum (Type AB, non- heat inactivated) is delipidated by centrifugation before use. The serum is then diluted to 25% with RPMI tissue culture media and used to test peptide stability. At predetermined time intervals a small amount of reaction solution is removed and added to either 6% aqueous trichloracetic acid or ethanol. The cloudy reaction sample is cooled (4°C) for 15 minutes and then spun to pellet the precipitated serum proteins. The presence of the peptides is then determined by reversed-phase HPLC using stability-specific chromatography conditions. The peptides of the present invention or analogs thereof which have CTL stimulating activity may be modified to provide desired attributes other than improved serum half life. For instance, the ability of the peptides to induce CTL activity can be enhanced by linkage to a sequence which contains at least one epitope that is capable of inducing a T helper cell response. Particularly preferred immunogenic peptides/T helper conjugates are linked by a spacer molecule. The spacer is typically comprised of relatively small, neutral molecules, such as amino acids or amino acid mimetics, which are substantially uncharged under physiological conditions. The spacers are typically 00 04655 45 selected from, e.g., Ala, Gly, or other neutral spacers of nonpolar amino acids or neutral polar amino acids. It will be understood that the optionally present spacer need not be comprised of the same residues and thus may be a hetero- or homo-oligomer. When present, the spacer will usually be at least one or two residues, more usually three to six residues. Alternatively, the CTL peptide may be linked to the T helper peptide without a spacer. The immunogenic peptide may be linked to the T helper peptide either directly or via a spacer either at the amino or carboxy terminus of the CTL peptide. The amino terminus of either the immunogenic peptide or the T helper peptide may be acylated. Exemplary T helper peptides include tetanus toxoid 830-843, influenza 307- 319, malaria circumsporozoite 382-398 and 378-389. In some embodiments it may be desirable to include in the pharmaceutical compositions of the invention at least one component which primes CTL. Lipids have been identified as agents capable of priming CTL in vivo against viral antigens. For example, palmitic acid residues can be attached to the alpha and epsilon amino groups of a Lys residue and then linked, e.g., via one or more linking residues such as Gly, Gly- Gly-, Ser, Ser-Ser, or the like, to an immunogenic peptide. The lipidated peptide can then be injected directly in a micellar form, incorporated into a liposome or emulsified in an adjuvant, e.g., incomplete Freund's adjuvant. In a preferred embodiment a particularly effective immunogen comprises palmitic acid attached to alpha and epsilon amino groups of Lys, which is attached via linkage, e.g., Ser-Ser, to the amino terminus of the immunogenic peptide. As another example of lipid priming of CTL responses, E. coli lipoproteins, such as tripalmitoyl-S-glycerylcysteinlyseryl-serine (P3CSS) can be used to prime virus specific CTL when covalently attached to an appropriate peptide. See, Deres et al., Nature 342:561-564 (1989), incorporated herein by reference. Peptides of the invention can be coupled to P 3 CSS, for example, and the lipopeptide administered to an individual to specifically prime a CTL response to the target antigen. Further, as the induction of neutralizing antibodies can also be primed with P 3 CSS conjugated to a peptide which displays an appropriate epitope, the two compositions can be combined to more effectively elicit both humoral and cell-mediated responses to infection. In addition, additional amino acids can be added to the termini of a peptide to provide for ease of linking peptides one to another, for coupling to a carrier support, or 00 04655 46 larger peptide, for modifying the physical or chemical properties of the peptide or oligopeptide, or the like. Amino acids such as tyrosine, cysteine,' lysine, glutamic or aspartic acid, or the like, can be introduced at the C- or N-terminus of the peptide or oligopeptide. Modification at the C terminus in some cases may alter binding characteristics of the peptide. In addition, the peptide or oligopeptide sequences can differ from the natural sequence by being modified by terminal-NH 2 -acylation, e.g., by alkanoyl (C 1 -C 20 ) or thioglycolyl acetylation, terminal-carboxyl amidation, e.g., ammonia, methylamine, etc. In some instances these modifications may provide sites for linking to a support or other molecule. The peptides of the invention can be prepared in a wide variety of ways. Because of their relatively short size, the peptides can be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols. See, for example, Stewart and Young, Solid Phase Peptide Synthesis, 2d. ed., Pierce Chemical Co. (1984), supra. Alternatively, recombinant DNA technology may be employed wherein a nucleotide sequence which encodes an immunogenic peptide of interest is inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression. These procedures are generally known in the art, as described generally in Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, New York (1982), which is incorporated herein by reference. Thus, fusion proteins which comprise one or more peptide sequences of the invention can be used to present the appropriate T cell epitope. As the coding sequence for peptides of the length contemplated herein can be synthesized by chemical techniques, for example, the phosphotriester method of Matteucci et al., J. Am. Chem. Soc. 103:3185 (1981), modification can be made simply by substituting the appropriate base(s) for those encoding the native peptide sequence. The coding sequence can then be provided with appropriate linkers and ligated into expression vectors commonly available in the art, and the vectors used to transform suitable hosts to produce the desired fusion protein. A number of such vectors and suitable host systems are now available. For expression of the fusion proteins, the coding sequence will be provided with operably linked start and stop codons, promoter and terminator regions and usually a replication system to provide an expression vector for expression in the desired cellular host. For example, promoter sequences compatible with bacterial hosts are provided in plasmids containing convenient restriction sites for insertion of the desired coding sequence. The resulting expression vectors are transformed into suitable bacterial hosts. Of course, yeast or mammalian cell hosts may also be used, employing suitable vectors and control sequences. The peptides of the present invention and pharmaceutical and vaccine compositions thereof are useful for administration to mammals, particularly humans, to treat and/or prevent viral infection and cancer. Examples of diseases which can be treated using the immunogenic peptides of the invention include prostate cancer, hepatitis B, hepatitis C, A DS, renal carcinoma, cervical carcinoma, lymphoma, CMV and condlyloma acuminatum. For pharmaceutical compositions, the immunogenic peptides of the invention are administered to an individual already suffering from cancer or infected with the virus of interest. Those in the incubation phase or the acute phase of infection can be treated with the immunogenic peptides separately or in conjunction with other treatments, as appropriate. In therapeutic applications, compositions are administered to a patient in an amount sufficient to elicit an effective CTL response to the virus or tumor antigen and to cure or at least partially arrest symptoms and/or complications. An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on, e.g., the peptide composition, the manner of administration, the stage and severity of the disease being treated, the weight and general state of health of the patient, and the judgment of the prescribing physician, but generally range for the initial immunization (that is for therapeutic or prophylactic administration) from about 1.0 μg to about 5000 μg of peptide for a 70 kg patient, followed by boosting dosages of from about 1.0 μg to about 1000 μg of peptide pursuant to a boosting regimen over weeks to months depending upon the patient's response and condition by measuring specific CTL activity in the patient's blood. It must be kept in mind that the peptides and compositions of the present invention may generally be employed in serious disease states, that is, life- threatening or potentially life threatening situations. In such cases, in view of the minimization of extraneous substances and the relative nontoxic nature of the peptides, it is possible and may be felt desirable by the treating physician to administer substantial excesses of these peptide compositions. For therapeutic use, administration should begin at the first sign of viral infection or the detection or surgical removal of tumors or shortly after diagnosis in the case of acute infection. This is followed by boosting doses until at least symptoms are substantially abated and for a period thereafter. In chronic infection, loading doses followed by boosting doses may be required. Treatment of an infected individual with the compositions of the invention may hasten resolution of the infection in acutely infected individuals. For those individuals susceptible (or predisposed) to developing chronic infection the compositions are particularly useful in methods for preventing the evolution from acute to chronic infection. Where the susceptible individuals are identified prior to or during infection, for instance, as described herein, the composition can be targeted to them, minimizing need for administration to a larger population. The peptide compositions can also be used for the treatment of chronic infection and to stimulate the immune system to eliminate virus-infected cells in carriers. It is important to provide an amount of immuno-potentiating peptide in a formulation and mode of administration sufficient to effectively stimulate a cytotoxic T cell response. Thus, for treatment of chronic infection, a representative dose is in the range of about 1.0 μg to about 5000 μg, preferably about 5 μg to 1000 μg for a 70 kg patient per dose. Immunizing doses followed by boosting doses at established intervals, e.g., from one to four weeks, may be required, possibly for a prolonged period of time to effectively immunize an individual. In the case of chronic infection, administration should continue until at least clinical symptoms or laboratory tests indicate that the viral infection has been eliminated or substantially abated and for a period thereafter. The pharmaceutical compositions for therapeutic treatment are intended for parenteral, topical, oral or local administration. Preferably, the pharmaceutical compositions are administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. Thus, the invention provides compositions for parenteral administration which comprise a solution of the immunogenic peptides dissolved or suspended in an acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers may be used, e.g., water, buffered water, 0.8% saline, 0.3% glycine, hyaluronic acid and the like. These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc. The concentration of CTL stimulatory peptides of the invention in the pharmaceutical formulations can vary widely, i.e., from less than about 0.1%, usually at or at least about 2% to as much as 20% to 50% or more by weight, and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected. The peptides of the invention may also be administered via liposomes, which serve to target the peptides to a particular tissue, such as lymphoid tissue, or targeted selectively to infected cells, as well as increase the half-life of the peptide composition. Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. In these preparations the peptide to be delivered is incorporated as part of a liposome, alone or in conjunction with a molecule which binds to, e.g., a receptor prevalent among lymphoid cells, such as monoclonal antibodies which bind to the CD45 antigen, or with other therapeutic or immunogenic compositions. Thus, liposomes either filled or decorated with a desired peptide of the invention can be directed to the site of lymphoid cells, where the liposomes then deliver the selected therapeutic/immunogenic peptide compositions. Liposomes for use in the invention are formed from standard vesicle-forming lipids, which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of, e.g., liposome size, acid lability and stability of the liposomes in the blood stream. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka et al., Ann. Rev. Biophvs. Bioeng. 9:467 (1980), U.S. Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, incorporated herein by reference. For targeting to the immune cells, a ligand to be incorporated into the liposome can include, e.g., antibodies or fragments thereof specific for cell surface determinants of the desired immune system cells. A liposome suspension containing a peptide may be administered intravenously, locally, topically, etc. in a dose which varies according to, inter alia, the manner of administration, the peptide being delivered, and the stage of the disease being treated. For solid compositions, conventional nontoxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable nontoxic composition is formed by incorporating any of the normally employed excipients, such as those carriers previously listed, and generally 10-95% of active ingredient, that is, one or more peptides of the invention, and more preferably at a concentration of 25%-75%. For aerosol administration, the immunogenic peptides are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of peptides are 0.01%-20% by weight, preferably 1%-10%. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%>. The balance of the composition is ordinarily propellant. A carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery. In another aspect the present invention is directed to vaccines which contain as an active ingredient an immunogenically effective amount of an immunogenic peptide as described herein. The peptide(s) may be introduced into a host, including humans, linked to its own carrier or as a homopolymer or heteropolymer of active peptide units. Such a polymer has the advantage of increased immunological reaction and, where different peptides are used to make up the polymer, the additional ability to induce antibodies and/or CTLs that react with different antigenic determinants of the virus or tumor cells. Useful carriers are well known in the art, and include, e.g., thyro globulin, albumins such as human serum albumin, tetanus toxoid, polyamino acids such as poly(lysine:glutamic acid), influenza, hepatitis B virus core protein, hepatitis B virus recombinant vaccine and the like. The vaccines can also contain a physiologically tolerable (acceptable) diluent such as water, phosphate buffered saline, or saline, and further typically include an adjuvant. Adjuvants such as incomplete Freund's adjuvant, aluminum phosphate, aluminum hydroxide, or alum are materials well known in the art. And, as mentioned above, CTL responses can be primed by conjugating peptides of the invention to lipids, such as P 3 CSS. Upon immunization with a peptide composition as described herein, via injection, aerosol, oral, transdermal or other route, the immune system of the host responds to the vaccine by producing large amounts of CTLs specific for the desired antigen, and the host becomes at least partially immune to later infection, or resistant to developing chronic infection. Vaccine compositions containing the peptides of the invention are administered to a patient susceptible to or otherwise at risk of viral infection or cancer to elicit an immune response against the antigen and thus enhance the patient's own immune response capabilities. Such an amount is defined to be an "immunogenically effective dose." In this use, the precise amounts again depend on the patient's state of health and weight, the mode of administration, the nature of the formulation, etc., but generally range from about 1.0 μg to about 5000 μg per 70 kilogram patient, more commonly from about 10 μg to about 500 μg mg per 70 kg of body weight. Xn some instances it may be desirable to combine the peptide vaccines of the invention with vaccines which induce neutralizing antibody responses to the virus of interest, particularly to viral envelope antigens. For therapeutic or immunization purposes, nucleic acids encoding one or more of the peptides of the invention can also be administered to the patient. A number of methods are conveniently used to deliver the nucleic acids to the patient. For instance, the nulceic acid can be delivered directly, as "naked DNA". This approach is described, for instance, in Wolff et. al., Science 247:1465-1468 (1990) as well as U.S. Patent Nos. 5,580,859 and 5,589,466. The nucleic acids can also be administered using ballistic delivery as described, for instance, in U.S. Patent No. 5,204,253. Particles comprised solely of DNA can be administered. Alternatively, DNA can be adhered to particles, such as gold particles. The nucleic acids can also be delivered complexed to cationic compounds, such as cationic lipids. Lipid-mediated gene delivery methods are described, for instance, in WO 96/18372; WO 93/24640; Mannino and Gould-Fogerite (1988) BioTechniques 6(7):682-691; Rose U.S. Pat No. 5,279,833; WO 91/06309; and Feigner et al. (1987) Proc. Natl. Acad. Sci. USA 84: 7413-7414. The peptides of the invention can also be expressed by attenuated viral hosts, such as vaccinia or fowlpox. This approach involves the use of vaccinia virus as a vector to express nucleotide sequences that encode the peptides of the invention. Upon introduction into an acutely or chronically infected host or into a noninfected host, the recombinant vaccinia virus expresses the immunogenic peptide, and thereby elicits a host CTL response. Vaccinia vectors and methods useful in immunization protocols are described in, e.g. J.S. Patent No. 4,722,848, incorporated herein by reference. Another vector is BCG (Bacille Calmette Guerin). BCG vectors are described in Stover et al. (Nature 351:456-460 (1991)) which is incorporated herein by reference. A wide variety of other vectors useful for therapeutic administration or immunization of the peptides of the invention, e.g., Salmonella typhi vectors and the like, will be apparent to those skilled in the art from the description herein. A preferred means of administering nucleic acids encoding the peptides of the invention uses minigene constructs encoding multiple epitopes of the invention. To create a DNA sequence encoding the selected CTL epitopes (minigene) for expression in human cells, the amino acid sequences of the epitopes are reverse translated. A human codon usage table is used to guide the codon choice for each amino acid. These epitope- encoding DNA sequences are directly adjoined, creating a continuous polypeptide sequence. To optimize expression and/or immunogenicity, additional elements can be incorporated into the minigene design. Examples of amino acid sequence that could be reverse translated and included in the minigene sequence include: helper T lymphocyte epitopes, a leader (signal) sequence, and an endoplasmic reticulum retention signal. In addition, MHC presentation of CTL epitopes may be improved by including synthetic (e.g. poly-alanine) or naturally-occurring flanking sequences adjacent to the CTL epitopes. The minigene sequence is converted to DNA by assembling oligonucleotides that encode the plus and minus strands of the minigene. Overlapping oligonucleotides (30-100 bases long) are synthesized, phosphorylated, purified and annealed under appropriate conditions using well known techniques, he ends of the oligonucleotides are joined using T4 DNA ligase. This synthetic minigene, encoding the CTL epitope polypeptide, can then cloned into a desired expression vector. Standard regulatory sequences well known to those of skill in the art are included in the vector to ensure expression in the target cells. Several vector elements are required: a promoter with a down-stream cloning site for minigene insertion; a polyadenylation signal for efficient transcription termination; an E. coli origin of replication; and an E. coli selectable marker (e.g. ampicillin or kanamycin resistance). Numerous promoters can be used for this purpose, e.g., the human cytomegalovirus (hCMV) promoter. See, U.S. Patent Nos. 5,580,859 and 5,589,466 for other suitable promoter sequences. Additional vector modifications may be desired to optimize minigene expression and immunogenicity. In some cases, introns are required for efficient gene expression, and one or more synthetic or naturally-occurring introns could be incorporated into the transcribed region of the minigene. The inclusion of rnRNA stabilization sequences can also be considered for increasing minigene expression. It has recently been proposed that immunostimulatory sequences (ISSs or CpGs) play a role in the immunogenicity of DNA vaccines. . These sequences could be included in the vector, outside the minigene coding sequence, if found to enhance immunogenicity. In some embodiments, a bioistronic expression vector, to allow production of the minigene-encoded epitopes and a second protein included to enhance or decrease immunogenicity can be used. Examples of proteins or polypeptides that could beneficially enhance the immune response if co-expressed include cytokines (e.g., IL2, IL12, GM-CSF), cytokine-inducing molecules (e.g. LeLF) or costimulatory molecules. Helper (HTL) epitopes could be joined to intracellular targeting signals and expressed separately from the CTL epitopes. This would allow direction of the HTL epitopes to a cell compartment different than the CTL epitopes. If required, this could facilitate more efficient entry of HTL epitopes into the MHC class II pathway, thereby improving CTL induction. In contrast to CTL induction, specifically decreasing the immune response by co-expression of immunosuppressive molecules (e.g. TGF-β) may be beneficial in certain diseases. Once an expression vector is selected, the minigene is cloned into the polylinker region downstream of the promoter. This plasmid is transformed into an appropriate E. coli strain, and DNA is prepared using standard techniques. The orientation and DNA sequence of the minigene, as well as all other elements included in the vector, are confirmed using restriction mapping and DNA sequence analysis. Bacterial cells harboring the correct plasmid can be stored as a master cell bank and a working cell bank. Therapeutic quantities of plasmid DNA are produced by fermentation in E. coli, followed by purification. Aliquots from the working cell bank are used to inoculate fermentation medium (such as Terrific Broth), and grown to saturation in shaker flasks or a bioreactor according to well known techniques. Plasmid DNA can be purified using standard bioseparation technologies such as solid phase anion-exchange resins supplied by Quiagen. If required, supercoiledDNA can be isolated from the open circular and linear forms using gel electrophoresis or other methods. Purified plasmid DNA can be prepared for injection using a variety of formulations. The simplest of these is reconstitution of lyophilized DNA in sterile phosphate-buffer saline (PBS). A variety of methods have been described, and new techniques may become available. As noted above, nucleic acids are conveniently formulated with cationic lipids. In addition, glycolipids, fusogenic liposomes, peptides and compounds referred to collectively as protective, interactive, non-condensing (PLNC) could also be complexed to purified plasmid DNA to influence variables such as stability, intramuscular dispersion, or trafficking to specific organs or cell types. Target cell sensitization can be used as a functional assay for expression and MHC class I presentation of mimgene-encoded CTL epitopes. The plasmid DNA is introduced into a mammalian cell line that is suitable as a target for standard CTL chromium release assays. The transfection method used will be dependent on the final formulation. Electroporation can be used for "naked" DNA, whereas cationic lipids allow direct in vitro transfection. A plasmid expressing green fluorescent protein (GFP) can be co-transfected to allow enrichment of transfected cells using fluorescence activated cell sorting (FACS). These cells are then chromium-51 labeled and used as target cells for epitope-specific CTL lines. Cytolysis, detected by 51Cr release, indicates production of MHC presentation of minigene-encoded CTL epitopes. In vivo immunogenicity is a second approach for functional testing of minigene DNA formulations. Transgenic mice expressing appropriate human MHC molecules are immunized with the DNA product. The dose and route of administration are formulation dependent (e.g. LM for DNA in PBS, LP for lipid-complexed DNA). Twenty-one days after immunization, splenocytes are harvested and restimulated for 1 week in the presence of peptides encoding each epitope being tested. These effector cells (CTLs) are assayed for cytolysis of peptide-loaded, chromium-51 labeled target cells using standard techniques. Lysis of target cells sensitized by MHC loading of peptides corresponding to minigene-encoded epitopes demonstrates DNA vaccine function for in vivo induction of CTLs. Antigenic peptides may be used to elicit CTL ex vivo, 'as well. The resulting CTL, can be used to treat chronic infections (viral or bacterial) or tumors in patients that do not respond to other conventional forms of therapy, or will not respond to a peptide vaccine approach of therapy. Ex vivo CTL responses to a particular pathogen (infectious agent or tumor antigen) are induced by incubating in tissue culture the patient's CTL precursor cells (CTLp) together with a source of antigen-presenting cells (APC) and the appropriate immunogenic peptide. After an appropriate incubation time (typically 1-4 weeks), in which the CTLp are activated and mature and expand into effector CTL, the cells are infused back into the patient, where they will destroy their specific target cell (an infected cell or a tumor cell). In order to optimize the in vitro conditions for the generation of specific cytotoxic T cells, the culture of stimulator cells is maintained in an appropriate serum-free medium. Prior to incubation of the stimulator cells with the cells to be activated, e.g., precursor CD8+ cells, an amount of antigenic peptide is added to the stimulator cell culture, of sufficient quantity to become loaded onto the human Class I molecules to be expressed on the surface of the stimulator cells. In the present invention, a sufficient amount of peptide is an amount that will allow about 200, and preferably 200 or more, human Class I MHC molecules loaded with peptide to be expressed on the surface of each stimulator cell. Preferably, the stimulator cells are incubated with >20μg/ml peptide. Resting or precursor CD8+ cells are then incubated in culture with the appropriate stimulator cells for a time period sufficient to activate the CD8+ cells. Preferably, the CD8+ cells are activated in an antigen-specific manner. The ratio of resting or precursor CD 8+ (effector) cells to stimulator cells may vary from individual to individual and may further depend upon variables such as the amenability of an individual's lymphocytes to culturing conditions and the nature and severity of the disease condition or other condition for which the within-described treatment modality is used. Preferably, however, the lymphocyte:stimulator cell ratio is in the range of about 30:1 to 300:1. The effector/stimulator culture may be maintained for as long a time as is necessary to stimulate a therapeutically useable or effective number of CD8+ cells. The induction of CTL in vitro requires the specific recognition of peptides that are bound to allele specific MHC class I molecules on APC. The number of specific MHC/peptide complexes per APC is crucial for the stimulation of CTL, particularly in primary immune responses. While small amounts of peptide/MHC complexes per cell are sufficient to render a cell susceptible to lysis by CTL, or to stimulate a secondary CTL response, the successful activation of a CTL precursor (pCTL) during primary response requires a significantly higher number of MHC/peptide complexes. Peptide loading of empty major histocompatability complex molecules on cells allows the induction of primary cyto toxic T lymphocyte responses. Peptide loading of empty major histocompatability complex molecules on cells enables the induction of primary cytotoxic T lymphocyte responses. Since mutant cell lines do not exist for every human MHC allele, it is advantageous to use a technique to remove endogenous MHC-associated peptides from the surface of APC, followed by loading the resulting empty MHC molecules with the immunogenic peptides of interest. The. use of non-transformed (non-tumorigenic), non- infected cells, and preferably, autologous cells of patients as APC is desirable for the design of CTL induction protocols directed towards development of ex vivo CTL therapies. This application discloses methods for stripping the endogenous MHC- associated peptides from the surface of APC followed by the loading of desired peptides. A stable MHC class I molecule is a trimeric complex formed of the following elements: 1) a peptide usually of 8 - 10 residues, 2) a transmembrane heavy polymorphic protein chain which bears the peptide-binding site in its αl and α2 domains, and 3) a non-covalently associated non-polymorphic light chain, β 2 microglobulin. Removing the bound peptides and/or dissociating the β 2 microglobulin from the complex renders the MHC class I molecules nonfunctional and unstable, resulting in rapid degradation. All MHC class I molecules isolated from PBMCs have endogenous peptides bound to them. Therefore, the first step is to remove all endogenous peptides bound to MHC class I molecules on the APC without causing their degradation before exogenous peptides can be added to them. Two possible ways to free up MHC class I molecules of bound peptides include lowering the culture temperature from 37°C to 26°C overnight to destabilize β 2 microglobulin and stripping the endogenous peptides from the cell using a mild acid treatment. The methods release previously bound peptides into the extracellular environment allowing new exogenous peptides to bind to the empty class I molecules. The cold-temperature incubation method enables exogenous peptides to bind efficiently to the MHC complex, but requires an overnight incubation at 26°C which may slow the cell's metabolic rate. It is also likely that cells not actively synthesizing MHC molecules (e.g., resting PBMC) would not produce high amounts of empty surface MHC molecules by the cold temperature procedure. Harsh acid stripping involves extraction of the peptides with trifluoroacetic acid, pH 2, or acid denaturation of the immuno affinity purified class I-peptide complexes. 1 These methods are not feasible for CTL induction, since it is important to remove the endogenous peptides while preserving APC viability and an optimal metabolic state which is critical for antigen presentation. Mild acid solutions of pH 3 such as glycine or citrate-phosphate buffers have been used to identify endogenous peptides and to identify tumor associated T cell epitopes. The treatment is especially effective, in that only the MHC class I molecules are destabilized (and associated peptides released), while other surface antigens remain intact, including MHC class π molecules. Most importantly, treatment of cells with the mild acid solutions do not affect the cell's viability or metabolic state. The mild acid treatment is rapid since the stripping of the endogenous peptides occurs in two minutes at 4°C and the APC is ready to perform its function after the appropriate peptides are loaded. The technique is utilized herein to make peptide- specific APCs for the generation of primary antigen-specific CTL. The resulting APC are efficient in inducing peptide-specific CD8+ CTL. Activated CD8+ cells may be effectively separated from the stimulator cells using one of a variety of known methods. For example, monoclonal antibodies specific for the stimulator cells, for the peptides loaded onto the stimulator cells, or for the CD8+ cells (or a segment thereof) may be utilized to bind their appropriate complementary ligand. Antibody-tagged molecules may then be extracted from the stimulator-effector cell admixture via appropriate means, e.g., via well-known immunoprecipitation or immunoassay methods. Effective, cytotoxic amounts of the activated CD8+ cells can vary between in vitro and in vivo uses, as well as with the amount and type of cells that are the ultimate target of these killer cells. The amount will also vary depending on the condition of the patient and should be determined via consideration of all appropriate factors by the practitioner. Preferably, however, about 1 X 10 6 to about 1 X 10 12 , more preferably about 1 X 10 8 to about 1 X 10 π , and even more preferably, about 1 X 10 9 to about 1 X 10 10 activated CD8+ cells are utilized for adult humans, compared to about 5 X 10 - 5 X 10 cells used in mice. Preferably, as discussed above, the activated CD8+ cell ' s are harvested from the cell culture prior to administration of the CD8+ cells to, the individual being treated. It is important to note, however, that unlike other present and proposed treatment modalities, the present method uses a cell culture system that is not tumorigenic. Therefore, if complete separation of stimulator cells and activated CD8+ cells is not achieved, there is no inherent danger known to be associated with the administration of a small number of stimulator cells, whereas administration of mammalian tumor-promoting cells may be extremely hazardous. Methods of re-introducing cellular components are known in the art and include procedures such as those exemplified in U.S. Patent No. 4,844,893 to Honsik, et al. and U.S. Patent No. 4,690,915 to Rosenberg. For example, administration of activated CD8+ cells via intravenous infusion is appropriate. The immunogenic peptides of this invention may also be used to make monoclonal antibodies. Such antibodies may be useful as potential diagnostic or therapeutic agents. The peptides may also find use as diagnostic reagents. For example, a peptide of the invention may be used to determine the susceptibility of a particular individual to a treatment regimen which employs the peptide or related peptides, and thus may be helpful in modifying an existing treatment protocol or in determining a prognosis for an affected individual. In addition, the peptides may also be used to predict which individuals will be at substantial risk for developing chronic infection. To identify peptides of the invention, class I antigen isolation, and isolation and sequencing of naturally processed peptides was carried out as described in the related applications. These peptides were then used to define specific binding motifs for each of the following alleles A3.2, Al , Al 1 , and A24.1. These motifs are described on page 3, above. The motifs described in Tables 8-11, below, are defined from pool sequencing data of naturally processed peptides as described in the related applications. TABLE 8 Summary HLA-A3.2 Allele-Snecific Motif Position Conserved Residues 1 V,L,M Y,D I 8 Q,N 9 K 10 K TABLE 9 Summary HLA-Al Allele-Soecific Motif Position Conserved Residues 1 - 2 s,τ 3 D,E 4 P 5 - 6 - 7 L 8 - 9 Y 10 K TABLE 10 Summary HLA-Al 1 AUele-Specific Motif Position Conserved Residues 1 2 T,V M,F 5 6 7 8 Q 9 K 10 K TABLE 11 Summary HLA-A24.1 AUele-Specific Motif Position Conserved Residues 1 2 Y 3 I,M 4 D,E,G,K,P 5 L,M,N 6 V 7 N.V 8 A,E,K,Q,S 9 F,L 10 F,A Example 2 Identification of immunogenic peptides Using the motifs identified above for various MHC class I allele amino acid sequences from various pathogens and tumor-related proteins were analyzed for the presence of these motifs. Screening was carried out described in the related applications. Table 12 provides the results of searches of the antigens. Table 12 Peptide AA Sequence Source A*0301 ' Α*1101 28.0719 10 ILEQWVAGRK HDV.nuc.16 0.0170 0.0012 28.0727 10 LSAGGKNLSK HDV.nuc.115 0.0097 0.0150 1259.02 11 STDTVDTVLEK Flu.HA.29 0.0001 0.0670 1259.04 9 GLAPLQLGK Flu.HA.63 0.6100 0.2000 1259.06 10 VTAACSHAGK Flu.HA.149 0.0380 0.0490 1259.08 9 GIHHPSNSK Flu.HA.195 0.1300 0.0140 1259.10 10 RMNYYWTLLK Flu.HA.243 2.5000 2.3000 1259.12 11 ITNKVNSVIEK Flu'.HA.392 0.0200 0.0670 1259.13 11 KMNIQFTAVGK Flu.HA.402 0.0280 0.0092 1259.14 9 NIQFTAVGK Flu.HA.404 0.0017 0.0330 1259.16 • 11 AVGKEFNKLEK Flu.HA.409 0.0210 0.0460 1259.19 11 KVKSQLKNNAK Flu.HA.465 0.0470 0.0031 1 * 259.20 11 SVRNGTYDYPK Flu.HA.495 0.0410 0.1400 1259.21 9 SHPSGPLK Flu.VMTl.13 0.7800 8.8000 1259.25 10 RMVLASTTAK Flu.VMTl.178 0.5500 0.0350 1259.26 9 MVLASTTAK Flu.VMTl.179 1.7000 1.4000 1259.28 10 RMGVQMQRFK Flu.VMTl.243 0.1000 0.0059 1259.33 10 ATELRASVGK Flu.VNUC.22 0.1400 0.3000 1259.37 11 TMVMELVRMIK Flu.VNUC.188 0.0890 0.0310 1259.43 10 RVLSFLKGTK Flu.VNUC.342 0.8000 0.0830 F119.01 9 MSLQRQFLR ORF3P 0.2000 0.7200 FI 19.02 9 LLGPGRPYR TRP.197 0.0190 0.0091 F119.03 9 LLGPGRPYK TRP.197K9 2.2000 0.6800 34.0019 8 RVYPELPK CEA.139 0.0130 0.0440 34.0020 8 TVSAELPK CEA.495 0.0037 0.0320 34.0021 8 TVYAEPPK CEA.317 0.0160 0.0220 34.0029 8 TLNYTLWR MAGE2.74 0.0140 0.0550 34.0030 8 LVHFLLLK MAGE2.116 0.0290 0.1500 34.0031 8 SVFAHPRK MAGE2.237 0.1410 0.0810 34.0043 8 KVLHHMVK MAGE3.285 0.0580 0.0190 34.0050 8 RVCACPGR p53.273 0.3500 0.0490 34.0051 8 KMFCQLAK p53.132 0.3800 ' ' 0.3600 34.0062 8 RAHSSHLK p53.363 0.5500 0.0071 34.0148 9 FVSNLATGR CEA.656 0.0019 0.0490 34.0152 9 RLQLSNGNK CEA.546 0.0250 0.0110 34.0153 9 RΓNGΓPQQK CEA.628 0.0400 0.0780 34.0154 9 KΓRKYTMRK HER2/neu.681 0.0620 0.0055 34.0155 9 LVHFLLLKK MAGE2.116 0.5220 1.4000 34.0156 9 SMLEVFEGK MAGE2.226 0.0950 1.6000 34.0157 9 SSFSTTLNK MAGE2.69 0.1600 2.0000 34.0158 9 TSYVKVLHK MAGE2.281 0.5300 0.1500 34.0159 9 VΓFSKASEK MAGE2.149 0.4900 0.0530 34.0160 9 GSWGNWQK MAGE3.130 0.0040 0.2060 34.0161 9 SSLPTTMNK MAGE3.69 0.6180 0.7100 34.0162 9 SVLEVFEGK MAGE3.226 0.1330 0.9000 34.0171 9 SSBMGGMNK p53.240 0.5440 1.1000 34.0172 9 SSCMGGMNK p53.240 0.0090 0.0490 34.0211 10 RTLTLFNVTK CEA.554 0.2200 1.3000 34.0212 10 TISPLNTSYK CEA.241 0.1800 0.0330 34.0214 10 STTXNYTLWK MAGE2.72 0.0870 0.6500 34.0215 10 ASSLPTTMNK MAGE3.68 0.0420 0.0270 34.0225 10 KTYQGSYGFK p53.101 0.4900 0.4200 34.0226 10 WRRBPHHEK p53.172 0.1800 0.2100 34.0228 10 GLAPPQHLΓK p53.187 0.0570 0.0160 34.0229 10 NSSCMGGMNK p53.239 0.0071 0.0290 34.0230 10 SSBMGGMNRK p53.240 0.0420 0.1600 34.0232 10 RVCACPGRDK p53.273 0.0190 0.0250 34.0295 11 KTITVSAELPK CEA.492 0.3600 0.1600 34.0296 11 TTITVYAEPPK CEA.314 0.0200 0.0280 34.0298 11 PTISPSYTYYR CEA.418 (0.0002) 0.1300 34.0301 11 GLLGDNQVMPK MAGE2.188 0.0780 0.0047 34.0306 11 MVELVHFLLLK MAGE2.113 0.0200 0.0120 34.0308 11 FSTTLNYTLWR MAGE2.71 0.0110 0.0170 4.0311 11 GLLGDNQLMPK MAGE3.188 0.1300 ' ' 0.0570 4.0317 11 RLGFLHSGTAK p53.110 0.0430 0.0001 4.0318 11 ALNKMFCQLAK p53.129 0.4400 0.0420 4.0323 11 RVCACPGRDRR p53.273 0.0290 0.0290 4.0324 11 LSQETFSDLWK p53.14 (0.0009) 0.0470 4.0328 11 RAHSSHLKSKK p53.363 0.0270 0.0038 4.0329 11 VTCTYSPALNK p53.122 0.0700 0.1200 4.0330 11 GTRVRAMAIYK p53.154 1.1000 0.3300 4.0332 11 STSPJLKKLMFK p53.376 0.3100 0.1300 0.0107 9 LAARNVLVK Her2/neu.846 0.0580 0.0285 0.0109 9 MALESILRR Her2/neu.889 0.0034 0.0237 0.0145 10 ISWLGLRSLR Her2/neu.450 0.0410 0.0027 40.0147 10 GSGAFGTVYK Her2/neu.727 0.0660 0.1300 40.0153 10 ASPLDSTFYR Her2/neu.997 0.0003 0.0670 Example 3 Identification of immunogenic peptides Using the B7-like supermotifs identified in the related applications described above, sequences from various pathogens and tumor-related proteins were analyzed for the presence of these motifs. Screening was carried out described in the related applications. Table 13 provides the results of searches of the antigens. Table 13 Peptide Sequence Source 40.0013 SPGLSAGI CEA.680I8 40.0022 KPYDGΓPA Her2/neu.921 40.0023 KPYDGΓPI Her2/neu.921I8 40.0050 APRMPEAA p53.63 40.0051 APRMPEAI p53.63I8 40.0055 APAAPTPI p53.76I8 0.0057 APTPAAPI p53.79I8 0.0059 TPAAPAPI p53.81I8 . 0.0061 APAPAPSI p53.84I8 0.0062 SPALNKMF p53.127 0.0063 SPALNKMI p53.127I8 40.0117 SPSAPPHRI CEA.3I9 40.0119 PPHRWCIPI CEA.7I9 40.0120 GPAYSGREI CEA.92 40.0156 MPNQAQMRILI Her2/neu.706I10 40.0157 MPYGCLLDHVI Her2/neu.801I10 40.0161 APPHRWCIPW , CEA.6 40.0162 APPHRWCLPI CEA.6I10 40.0163 LPWQRLLLTA CEA.13 40.0164 IPWQRLLLTI CEA.13110 40.0166 LPQHLFGYSI CEA.58I10 40.0201 RPRFRELVSEF Her2/neu.966 40.0202 RPRFRELVSEI Her2/neu.966Ill 40.0205 PPSPREGPLPA Her2/neu.ll49 40.0206 PPSPREGPLPI Her2/neu.1149111 40.0207 GPLPAARPAGA Her2/neu.ll55 40.0208 GPLPAARPAGI Her2/neu.1155111 40.0231 APAPAAPTPAA p53.74 40.0232 APAPAAPTPAI p53.74Il l 40.0233 APAAPTPAAPA p53.76 40.0234 APAAPTPAAPI p53.76Ill 45.0003 LPWQRLLI CEA.13.18 45.0004 LPQHLFGI CEA58.I8 45.0007 RPGVNLSI CEA.428.I8 45.0010 LPQQHTQI CEA.632.I8 45.0011 TPNNNGTI CEA.646.I8 45.0016 CPLHNQEI Her2/neu.315.18 45.0017 KPCARVCI Her2/neu.336.I8 45.0019 WPDSLPDI Her2/neu.415.I8 5.0023 SPYVSRLI Her2/neu.779.I8 5.0024 VPLKWMAI Her2/neu.884.I8 45.0026 RPRFRELI Her2/neu.966.I8 45.0028 APGAGGMI Her2/neu.1036.18 5.0031 SPGKNGVI Her2/neu.1174.18 45.0037 SPQGASSI MAGE3.64.18 45.0038 YPLWSQSI MAGE3.77.18 45.0044 SPLPSQAI p53.33.I8 45.0046 MPEAAPPI p53.66.I8 45.0047 APAPSWPI p53.86.I8 45.0051 KPVEDKDAI CEA.155.I9 45.0054 IPQQHTQVI CEA.632.I9 45.0060 APPVAPAPI p53.70.I9 45.0062 APAAPTPAI p53.76.I9 45.0064 PPGTRVRAI p53.152.19 45.0065 APPQHLLRI p53.189.19 45.0071 IPQQHTQVLI CEA632.I10 45.0072 SPGLSAGATI CEA.680.I10 45.0073 SPMCKGSRCI Her2/neu.196.110 45.0074 MPNPEGRYTI Her2/neu.282.I10 45.0076 CPLHNQEVTI Her2/neu.315.110 45.0079 KPDLSYMPII Her2/neu.605.I10 45.0080 TPSGAMPNQI Her2/neu.701.I10 45.0084 GPASPLDSTI Her2/neu.995.I10 45.0091 APPVAPAPAI p53.70.I10 45.0092 APAPAAPTPI p53.74.I10 45.0093 APTPAAPAPI p53.79.I10 45.0094 APSWPLSSSI p53.88.I10 45.0103 APTISPLNTSI CEA.239.il 1 45.0108 SPSYTYYRPGI CEA.421.I11 45.0117 CPSGVKPDLSI Her2/neu.600.Ill 45.0118 SPLTSIISAVI Her2/neu.649.Ill 45.0119 ΓPDGENVKΓPI Her2/neu.740.Il l 5.0124 SPLDSTFYRSI Her2/neu.998.Ill ' 5.0128 LPAARPAGATI Her2/neu.1157.111 5.0134 HPRKLLMQDLI MAGE2.241.il 1 45.0135 GPRALIETSYI MAGE2.274.il 1 5.0139 GPRALVETSYI MAGE3.274.il 1 45.0140 APRMPEAAPPI p53.63.Ill 45.0141 VPSQKTYQGSI p53.97.Ill 1145.10 FPHCLAFAY HBV POL 541 analog 1145.09 FPVCLAFSY HBV POL 541 analog 26.0570 YPALMPLYACI HBV.pol.645 The above description is provided to illustrate the invention but not to limit its scope. Other variants of the invention will be readily apparent to, one of ordinary skill in the art and are encompassed by the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference.

Claims: WHAT IS CLAIMED IS: 1. A composition comprising an immunogenic peptide having an HLA-A2.1 binding motif, which immunogenic peptide is selected from a group consisting of: AILTFGSFV, HLRDFALAV, ALLGSIALL, ALLATILAA, LLATILAAV, RLFADELAA, YLSKCTLAV, LVYHIYSKL SMYLCILSA, YLCILSALV, VMFSYLQSL, RLHVYAYSA, GLQTLGAFV, FVEEQMTWA, QMTWAQTVV, IILDTALFV, ALFVCNAFV, AMGNRLVEA, RLVEACNLL TLSIVTFSL, KLSVLLLEV, LLLEVNRSV, FVSSPTLPV, AMLVLLAEI, QMARLAWEA, VLAIEGLFMA, YLYHPLLSPI, SLFEAMLANV, STTGLNQLGL, LAILTFGSFV, ALLGSIALLA, ALLATLLAAV, LLATILAAVA, RLFADELAAL, YLSKCTLAVL, LLVYHΓYSKI, SMYLCILSAL, HLHRQMLSFV, LLCGKTGAFL, ETLSrv FSL, VMCTYSPPL, KLFCQLAKT, ATPPAGSRV, FLQSGTAKSV, CMDRGLTVFV, VLLNWWRWRL, GVFTGLTHI, QMWKCLLRL, IMTCMSADL, ALAAYCLST, VLSGKPAII, FISGIQYLA, YTMTCMSADL, AIASLMAFTA, GLAGAAIGSV, MIGVLVGV, VLPLAYISL, SLGCLFFPL, PLAYISLFL, LMLFYQVWA, NISIYNYFV, NISVYNYFV, FVWTHYYSV, FLTWHRYHL, LTWHRYHLL, MLQEPSFSL, SLPYWNFAT, RLPEPQDVA, VTQCLEVRV, LLHTFTDAV, NMVPFWPPV, AVVGALLLV, AVVAALLLV, LLVAAJFGV, SMDEANQPL, VLPLAYISV, SLGCIFFPV, PLAYISLFV, LLLFQQARV, LMLFYQVWV : LLPSSGPGV, NLSIYNYFV, NLSVYNYFV, FLWTHYYSV, SLKKTFLGV, FLTWHRYHV, MLQEPSFSV, SLPYWNFAV, ALGKNVCDV, SLLISPNSV, SLFSQWRW, TLGTLCNSV, RLPEPQDW, VLQCLEVRV, 98 SLNSFRNTV, 99 SLDSFRNTV 100 FLNGTGGQV 101 VLLHTFTDV 102 ALVGALLLV 103 ALVAALLLV, 104 LLVALIFGV, 105 YLLRARRSV, 106 SMDEANQPV, 107 SLGCLFFPLL, 108 GMCCPDLSPV, 109 AACNQKILTV 110 FLTWHRYHLL, 111 SLHNLAHLFL 112 LLLVAALFGV 113 LLVAATFGVA, 114 ALΓFGTASYL, 115 SMDEANQPLL, 116 LLTDQYQCYA, 117 SLGCIFFPLV, 118 FLMLFYQVWV, 119 ALCDQRVLIV, 120 ALCNQKILTV, 121 FLTWHRYHLV, 122 SLHNLAHLFV, 123 NLAHLFLNGV, 124 NMVPFWPPW, 125 ILWAALLLV, 126 LLVALLFGTV, 127 ALΓFGTASYV, 128 SMDEANQPLV, 129 LLTDQYQCYV, 130 LLIQNIIQNDT, 131 IIQNDTGFYTL, 132 TLFNVTRNDTA 133 LTLLSVTRNDV 134 GLYTCQANNSA, 135 ATVGIMIGVLV, 136 GLVPPQHLΓRV, 137 GLAPPVHLΓRV, 138 GLAPPEHLΓRV, 139 ILIGVLVGV, 140 YLLMVKCWMV, 141 LLGRDSFEV, 142 FMYSDFHFI, 143 NMLSTVLGV 144 SLENFRAYV, 145 KMAELVHFV, 146 KLAELVHFV 147 VLIQRNPQV, 148 VLLGWFGV, 149 SLISAWGV, 150 YMIMVKBWMI, 151 YLIMVKBWMV, 152 KLWEELSVV, 153 AMBRWGLLV, 154 ILIGVLVGV, 155 ATVGUIGV, 156 SJPPPGTRV, 157 LVFGIELJEV, 158 ILGFVFTL, 159 KLFGSLAFL, 160 YLQLVFGIEV, 161 MMNDQLMFL, 162 ALVLAGGFFL, 163 WLCAGALVL, „,_„,„ „ PCT/US00/04655 72 164 MVFELANSI, 165 RMMNDQLMFL, 166 LVLAGGFFL, 167 VLAGGFFLL, 168 LLHETDSAV, 169 LMYSLVHNL, 170 QLMFLERAFI, 171 LMFLERAFI, 172 KLGSGNDFEV, 173 LLQERGVAYI, 174 GMPEGDLVYV, 175 FLDELKAENI, 176 ALFDLESKV, 177 and GLPSLPVHPI. 178 179 1 2. A method of inducing a cytotoxic T cell response against a 2 preselected antigen in a patient expressing an HLA-A2.1 MHC product, the method 3 comprising contacting cytotoxic T cells from the patient with a composition comprising 4 an immunogenic peptide selected from the group consisting of: 5 AILTFGSFV, 6 HLRDFALAV, 7 ALLGSIALL, 8 ALLATILAA, 9 LLATILAAV, 10 RLFADELAA, 11 . YLSKCTLAV, 12 LVYHIYSKI, 13 SMYLCLLSA, 14 YLCILSALV, 15 VMFSYLQSL, . 16 RLHVYAYSA, GLQTLGAFV, FVEEQMTWA, QMTWAQTVV, IILDTALFV, ALFVCNAFV, AMGNRLVEA, RLVEACNLL TLSΓV FSL, KLSVLLLEV, LLLEVNRSV, FVSSPTLPV, AMLVLLAEI, QMARLAWEA, VLAIEGLFMA, YLYHPLLSPI, SLFEAMLANV, STTGLNQLGL, LAILTFGSFV, ALLGSLALLA, ALLATILAAV, LLATILAAVA, RLFADELAAL, YLSKCTLAVL, LLVYHIYSKI, SMYLCLLSAL, HLHRQMLSFV, LLCGKTGAFL, ETLSΓVTFSL, VMCTYSPPL, KLFCQLAKT, ATPPAGSRV, FLQSGTAKSV, CMDRGLTVFV : VLLNWWRWRL, GVFTGLTHI, QMWKCLLRL, ΓMTCMSADL, ALAAYCLST, VLSGKPAH, FISGIQYLA, YLMTCMSADL, ALASLMAFTA, GLAGAAIGSV, MIGVLVGV, VLPLAYISL, SLGCIFFPL, PLAYISLFL, LMLFYQVWA, NISIYNYFV, NISVYNYFV, FVWTHYYSV, FLTWHRYHL, LTWHRYHLL, MLQEPSFSL, SLPYWNFAT, RLPEPQDVA, VTQCLEVRV, LLHTFTDAV, NMVPFWPPV, AWGALLLV, AWAALLLV, LLVAAJFGV, SMDEANQPL, VLPLAYISV, SLGCLFFPV, PLAYISLFV, 83 LLLFQQARV, 84 LMLFYQVWV, 85 LLPSSGPGV, 86 NLSIYNYFV, 87 NLSVYNYFV, 88 FLWTHYYSV, 89 SLKKTFLGV, 90 FLTWHRYHV, 91 MLQEPSFSV, 92 SLPYWNFAV, 93 ALGKNVCDV, 94 SLLISPNSV, 95 SLFSQWRVV, 96 TLGTLCNSV, 97 RLPEPQDW, 98 VLQCLEVRV, 99 SLNSFRNTV, 100 SLDSFRNTV 101 FLNGTGGQV 102 VLLHTFTDV 103 ALVGALLLV 104 ALVAALLLV, 105 LLVALLFGV, 106 YLIRARRSV, 107 SMDEANQPV, 108 SLGCΓFFPLL, 109 GMCCPDLSPV, 110 AACNQKILTV 111 FLTWHRYHLL 112 SLHNLAHLFL 113 LLLVAALFGV 114 LLVAAIFGVA, 115 ALΓFGTASYL, 116 SMDEANQPLL, 117 LLTDQYQCYA, 118 SLGCIFFPLV, 119 FLMLFYQVWV, 120 ALCDQRVLΓV, 121 ALCNQKΓLTV, 122 FLTWHRYHLV, 123 SLHNLAHLFV, 124 NLAHLFLNGV, 125 NMVPFWPPW, 126 ILVVAALLLV, 127 LLVALIFGTV, 128 ALIFGTASYV, 129 SMDEANQPLV, 130 LLTDQYQCYV, 131 LLIQNIIQNDT, 132 IIQNDTGFYTL, 133 TLFNVTRNDTA 134 LTLLSVTRNDV 135 GLYTCQANNSA, 136 ATVGIMIGVLV, 137 GLVPPQHLΓRV, 138 GLAPPVHLΓRV, 139 GLAPPEHLΓRV, 140 ILIGVLVGV, 141 YLΓMVKCWMV, 142 LLGRDSFEV, 143 FMYSDFHFI, 144 NMLSTVLGV 145 SLENFRAYV, 146 KMAELVHFV, 147 KLAELVHFV 148 VLIQRNPQV, 149 VLLGWFGV, 150 SLISAWGV, 151 YMIMVKBWMI, 152 YLIMVKBWMV, 153 KLWEELSW, 154 AMBRWGLLV, 155 UIGVLVGV, 156 ATVGDTGV, 157 SJPPPGTRV, 158 LVFGIELJEV, 159 ILGFVFTL, 160 KLFGSLAFL, 161 YLQLVFGIEV, 162 MMNDQLMFL, 163 ALVLAGGFFL, 164 WLCAGALVL, 165 MVFELANSI, 166 RMMNDQLMFL, 167 LVLAGGFFL, 168 VLAGGFFLL, 169 LLHETDSAV, 170 LMYSLVHNL, 171 QLMFLERAFI, 172 LMFLERAFI, 173 KLGSGNDFEV, 174 LLQERGVAYI, 175 GMPEGDLVYV, 176 FLDELKAENI, 177 ALFDIESKV, 178 and GLPSIPVHPI. 179 3. A composition comprising an immunogenic peptide selected from a group consisting of: RVYPELPK, TVSAELPK, TVYAEPPK, TLNYTLWR, LVHFLLLK, SVFAHPRK, KVLHHMVK, RVCACPGR, KMFCQLAK, RAHSSHLK, FVSNLATGR, RLQLSNGNK, RTNGIPQQK, KLRKYTMRK, LVHFLLLKK, SMLEVFEGK, SSFSTTINK, TSYVKVLHK, VIFSKASEK, GSWGNWQK, SSLPTTMNK, SVLEVFEGK, SSBMGGMNK, SSCMGGMNK, RTLTLFNVTK, TISPLNTSYK, STTLNYTLWK, ASSLPTTMNK, KTYQGSYGFK, VVRRBPHHEK, GLAPPQHLIK, NSSCMGGMNK, SSBMGGMNRK, RVCACPGRDK, KTITVSAELPK, TTITVYAEPPK, PTISPSYTYYR, GLLGDNQVMPK, MVELVHFLLLK, FSTTLNYTLWR, GLLGDNQΓMPK, RLGFLHSGTAK, ALNKMFCQLAK, RVCACPGRDRR, LSQETFSDLWK, RAHSSHLKSKK, VTCTYSPALNK, GTRVRAMAIYK, STSPHKKLMFK, LAARNVLVK, MALESILRR, ISWLGLRSLR, GSGAFGTVYK, and ASPLDSTFYR, 4. A method of inducing a cytotoxic T cell response against a preselected antigen in a patient, the method comprising contacting cytotoxic T cells from the patient with a composition comprising an immunogenic peptide selected from the group consisting of: RVYPELPK, TVSAELPK, TVYAEPPK, TLNYTLWR, LVHFLLLK, SVFAHPRK, KVLHHMVK, RVCACPGR, KMFCQLAK, RAHSSHLK, FVSNLATGR, RLQLSNGNK, RINGΓPQQK, KLRKYTMRK, LVHFLLLKK, SMLEVFEGK, SSFSTTLNK, TSYVKVLHK, VIFSKASEK, GSVVGNWQK, SSLPTTMNK, SVLEVFEGK, SSBMGGMNK, SSCMGGMNK, RTLTLFNVTK, TISPLNTSYK, STTLNYTLWK, ASSLPTTMNK, KTYQGSYGFK, VVRRBPHHEK, GLAPPQHLLK, NSSCMGGMNK, SSBMGGMNRK, RVCACPGRDK, KTITVSAELPK, TTITVYAEPPK, PTISPSYTYYR, GLLGDNQVMPK, MVELVHFLLLK, FSTTLNYTLWR, GLLGDNQLMPK, RLGFLHSGTAK, ALNKMFCQLAK, RVCACPGRDRR, LSQETFSDLWK, RAHSSHLKSKK, VTCTYSPALNK, GTRVRAMAIYK, STSRHKKLMFK, LAARNVLVK, MALESILRR, ISWLGLRSLR, GSGAFGTVYK, and ASPLDSTFYR. 5. A composition comprising an immunogenic peptide selected from a group consisting of the peptides listed in Table 13. 6. A method of inducing a cytotoxic T cell response against a preselected antigen in a patient, the method comprising contacting cytotoxic T cells from the patient with a composition comprising an immunogenic peptide selected from the group consisting of the peptides listed in Table 13.

Inventors: KAST W MARTIN, SETTE ALESSANDRO, SIDNEY JOHN, SOUTHWOOD SCOTT, KAST, W., MARTIN, SETTE, ALESSANDRO, SIDNEY, JOHN, SOUTHWOOD, SCOTT
Applicants: EPIMMUNE INC, EPIMMUNE INC.
Application year: 2000
Main classification: C07K7
IPC codes: A61K38, A61K39, A61P31, A61P35, A61P37, A61P43, C07K7