From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Vaccines and Immune Responses
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6638
Organization: unspecified
Date: Tue, 15 Dec 92 22:19:38 PST

                 IMMUNIZATION AND IMMUNE RESPONSES

Since HIV vaccines are in the news so often lately, I thought that this 
clear and concise explanation of the immune response and vaccines might 
be helpful.

----------------------------------------------------------------------
The following is from Chapter 8 "Prospects for vaccination against HIV 
infection" by K.H.G. Mills of "Immunology of HIV Infection " edited by 
A. Graham Bird and published by Kluwer Academic Publishers in 1992.

Mills' affiliation: Division of Immunology, NIBSC, Blanche Lane, South 
Mimms, Potters Bar, Herts EN6 3QJ, UK.

Pages 156-158:

NATURE OF A PROTECTIVE IMMUNE RESPONSE

The body responds to an invading microorganism such as a virus by the 
generation of humoral (B cell) and cell-mediated (T cell) immune 
responses directed against a variety of epitopes on the foreign 
antigens. Humoral response include the production of antibodies capable 
of binding to the virus and where the epitope is a functionally 
important region such as the receptor binding or membrane fusion domain 
of a viral surface protein, the antibody will be capable of neutralizing 
or preventing infectivity of the virus. Alternatively virally infected 
cells can be eliminated by mechanisms involving antibody-dependent 
cellular cytotoxicity (ADCC) natural killer (NK) cells or MHC-restricted 
cytotoxic T lymphocytes (CTL). Finally, the induction and regulation of 
these effector functions are dependent of lymphokines released by 
antigen-specific Th cells. Following encounter with foreign antigen, 
memory T and B cells are generated which enable the immune system to 
respond quickly to the microorganism bearing the foreign antigen and 
thereby eliminate it. This the theoretical basis of successful anti- 
viral vaccination strategies.

  Unlike antibodies which bind antigen directly, T cells recognize 
linear determinants on denatured antigen, in association with MHC 
proteins, following processing in an antigen-presenting cell (APC). In 
general, Th cells are CD4+ MHC class II-restricted and recognize 
exogenous antigen, processed in endosomes and readily provided by 
immunization with soluble antigen or shed from virally infected cells. 
In contrast CD8+ CTL are MHC class I-restricted and recognize antigen 
processed by the endogenous route following infection of the target cell 
with a replicating virus or in exceptional circumstances by immunization 
with synthetic peptides/lipopeptides or soluble proteins presented as 
immune stimulating complexes (ISCOMs). Therefore both the qualitative 
and the quantitative nature of an immune response generated by 
vaccination is dependent on the nature of the immunogen. Live vectors, 
lipid-based or particulate antigen-presenting systems each have their 
merits for stimulating different arms of the immune response.

  In most viral systems where a protective immune response has been 
demonstrated, antibodies against virus surface proteins are considered 
to play a key role. Although CTL have also been implicated in 
protection, their role is more likely to be in the control of disease 
progression through the clearance of virally infected cells. 
Furthermore, in certain viral diseases virus-specific CTL can contribute 
to disease pathology by the destruction of tissues expressing viral 
antigens.

PROTECTIVE IMMUNITY TO HIV

The possible mechanism of protective immunity to HIV remain to be 
defined. Following HIV infection in humans a wide range of humoral 
cellular immune responses are generated; antibodies mediating in vitro 
virus neutralization, inhibition of CD4-gp120 interaction or cellular 
cytotoxicity and cells mediating MHC-restricted and non-restricted lytic 
activity as well as helper function have all been documented. Although 
there is some indication that certain of these responses decline with 
disease progression, it is not clear which, if any, of these anti-HIV 
immune responses influence the course of infection. The ability of the 
virus to latently infect certain cells, to rapidly mutate its envelope 
protein in infected individuals and to induce antibodies which enhance 
infection may help it to escape a potentially protective immune 
response. Alternatively its tropism for the CD4+ T cell, which up- 
regulates almost all immune responses, may be a critical factor in the 
evasion of immunity. Indeed abnormal Th function has been documented in 
HIV-infected individuals long before a reduction in the number of CD4+ T 
cells is evident. This may be one of the major obstacles in attempts to 
control HIV infection by post-exposure immunotherapy. However, studies 
in animal models indicate that it should be possible to induce a 
protective immune response to at least a limited range of virus 
variants, by vaccination of seronegative individuals.

  In addition to studies of anti-HIV immunity in infected humans, 
extensive investigations have been reported on the immune responses to 
HIV proteins in experimental animals. An important component of a 
protective immune response to HIV is considered to be the neutralizing 
antibody response against the surface env glycoprotein. A large number 
of studies have centered on a hypervariable regions, called the V3 or 
GPGR loop, which appears to be the immunodominant neutralizing antibody 
epitope in HIV-infected individuals. However, antibodies to alternative 
functionally important and more conserved regions of env, such as the 
CD4 binding domain of gp120 or the region of gp41 implicated in fusion 
activity or antibodies mediating ADCC, may be required for a broadly 
protective immune response. Poor reproducibility of the in vitro HIV 
neutralization assay and an overemphasis on the use of synthetic 
peptides to map antibody epitopes has seriously compromised the search 
for the protective immune responses.

  In contrast to the humoral responses where the protective antibody 
epitopes are usually on the exposed regions of viral surface proteins, T 
cells can recognize conserved internal proteins as well as variable 
surface viral glycoproteins. MHC class I or class II-restricted T cell 
epitopes have been identified on HIV env, gag, pol and nef proteins. HIV 
gag-specific class I-restricted CD8+ CTL have been detected at high 
frequency in a large proportion of HIV-infected individuals, and there 
is some evidence the activity declines with disease progression. 
Furthermore there is evidence from in vitro experiments that CD8+ CTL 
can control HIV replication in CD4+ T cells. Although antibody responses 
to env are considered to be the main protective mechanism against HIV 
infection, it is possible that CTL, directed against early-expressed HIV 
regulatory proteins, may be able to eliminate the infected cell before 
release of new viral particles. In other viral infections, such as 
influenza, CTL have been shown to play a role in viral clearance and 
disease control. However, proposals to boost cellular responses to HIV 
in seropositive individuals by vaccination are complicated by the 
possible accelerated destruction of host cells with viral antigens 
absorbed to their surface. Furthermore, the requirements for a live 
vector, such as vaccinia virus recombinants, to generated CD8+ class 
I-restricted CTL, also carry the risk of Th cell activation which is 
known to increase their susceptibility to HIV.

  The role of HIV-specific MHC class II-restricted T cells in protective 
immunity to HIV is likely to be indirect, through the generation of 
anti-HIV antibodies by B cells and in the recall memory responses, where 
individuals are exposed to the virus at a time when the circulating 
antibody levels are low or undetectable. Although Th cell responses to 
HIV env, gag and pol have been demonstrated in HIV seropositive 
individuals, these responses are often weak and become undetectable as 
the infection progresses. In contrast, consistent HIV-specific Th cell 
activity has been demonstrated in HIV human volunteers and experimental 
animals following immunization with recombinant or native HIV proteins 
or live recombinant HIV vaccines.

  The fine specificity of Th cells that may be required for the 
generation of a protective immune response remains to be defined. Th 
cells specific for epitopes on any viral protein, including conserved 
regions of internal proteins, could theoretically regulate effector 
functions directed against putative protective epitopes on the more 
variable domains of the surface env glycoprotein. Studies in influenza 
and hepatitis B have shown that this type of intermolecular 
intrastructural antibody-T cell help can operate. However, a recent 
study has suggested that vaccination with recombinant HIV or SIV gag 
proteins, although capable of inducing gag-specific Th cells, did not 
result in the generation of an enhanced anti-env antibody response 
following a boost with inactivated HIV or challenge with live SIV. This 
may suggest that the Th cells and antibody epitopes critical for 
protection may be confined to the env glycoprotein. If correct, this 
will considerable complicate the effort to generate protective immunity 
to a wide range of HIV variants.
Newsgroups: sci.med.aids