The role of human leukocyte antigen E and G in HIV infection (2007)

Introduction An important area of HIV research is the immune response and how HIV circumvents it to create a successful and chronic infection. Various studies have provided not only a basic understanding of ‘how HIV invades’ but also clues for the development of vaccines to fight against AIDS. Although HIV initially evokes an immune response, it later escapes and evades the immune system for a successful infection. Methods of escape from the immune response include rapid mutations altering the organization of cell surface receptors, alterations in the expression profile of human leukocyte antigens (HLA) and destruction of immune effector cells. HIV infects through exchange of body fluids. The cells mainly infected by HIV are the T helper cells (CD4 T cells), dendritic cells and macrophages. This tropism is generated because HIV utilizes CD4 as a primary receptor plus a coreceptor: CCR5 (expressed on macrophages, dendritic cells and T cells) for the R5 HIV strain and CXCR4 (T cells) for the X4 strain [1]. At the early stages of infection, HIVR5 utilizing CCR5 predominates, whereas at the later stages HIVX4 using CXCR4 is mainly seen [2,3]. In the early stages of infection, the foremost target is CD4 T cells [4]. These cells along with other putative targets harbour mature virus and be carried in the circulation to lymph nodes and lymphoid organs. Here, the virions continue to infect immune cells, preferentially CD4 cells [5], in some more vigorous way as the density of target cells are higher at these places. This infection as well as the destruction of CD4 cells later on leads to a profound decrease in CD4 cell count. The sudden depletion in CD4 T cells is unlikely to be caused simply by direct viral-induced lysis as the number of cells infected initially may not be sufficient to account for the massive decrease observed [6]. It has been suggested that bystander apoptosis induced by viral antigens or cytokines [7,8] and downregulation of CD4 receptor by viral HIV-negative effector (Nef) protein [9,10] may be involved. Other studies have emphasized apoptosis mediated by CD95 (FAS) and CD95L [FAS ligand (FasL)], which, in turn, are stimulated by increased concentration of viral envelope protein gp120 during infection, as a mechanism to account for the preferential depletion of CD4 T cells [11,12]. With the continuing decrease in CD4 T cells, there is an explosive increase in virus production, which then evokes and is resisted by cellular immune response. After a peak of viral concentration has been reached, a gradual decrease is observed. Though activated cytotoxic T cells (CTL) can partially check infection [13], which is evident by the appearance by HIV-specific CTL, this counterattack does not eradicate HIV completely as replicating viruses can escape the CTL response by mutation of their activation markers [14] and through other mechanisms of immune escape. Some studies have suggested that this decline in virus concentration may be because of ‘substrate exhaustion’, as it is followed by depletion of CD4 T cells [15,16], which functions as a reservoir for viral dissemination. Cellular immune response to HIV infection HIV infection and intrusion of viral particles are counterattacked by CTL-mediated immune responses. Though the cellular immune response fails to control HIV-1 infection completely in most infected individuals, its occurrence is evident in regulating viral load during infection. During acute infection, reduction in viral load coincides with the appearance of HIV-specific CTL [17,18] and an inverse relationship is established between viral load and HIV-specific CTL [19]. The initial CTL response may be directed against a few epitopes, which subsequently broadens during prolonged antigen stimulation [20]. CTL could also be expected to have a role during chronic HIV-1 infection as HIV-1-specific T cells remain at high frequency [21,22]. The high concentration of these T cells may result from continued antigenic stimulation. This observation is supported by the fact that there is a steady decline in CTL as viraemia is reduced by HAART [23]. However, in chronic infection without treatment, a high number of HIV-1-specific CTL is seen. Though the CTL response occurs in early as well as in later stages of infection, the epitopes targeted during acute infection often differ from those recognized during chronic infection [20,24]. When CTL recognize self-HLA molecules loaded with foreign peptide, they activate Fas and secrete perforins and granzymes, which lyse target cells [25]. The CTL produces cytokines (interferon α and tumour necrosis factor α) that affect viral replication [26]. HIV-1-specific CTL also produce the CC chemokines macrophage inflammatory protein 1α and 1β and RANTES, which suppress HIV-1 replication [27]. Even with these various effector functions, CTL cannot completely check viral intrusion in the immune system. Immune escape of cytotoxic T cells As CTL do not carry CD4, the main receptor for viral entry and infection, they are anticipated to be a major player in HIV regulation. CTL can use multiple effector mechanisms to regulate viral replication [25,28], including lytic mechanisms and CC chemokine-mediated blockade of viral entry [29,30]. The existence of HIV-specific CTL and their successful involvement in protection against disease transmission confirms their importance in disease regulation [31,32]. As CTL can pose a strong regulatory force against HIV, virions that can escape the CTL response have a selection advantage. HIV has a high mutational rate (1 in 105 bases [33]) and so can produce many mutants, but only those mutants that do not cost in terms of viral fitness would be selected. These mutational escapes lead to failure of vaccines as well as of immune regulation, as escape variants do not generate specific CTL but keep on eliciting the proliferation of CTL specific for wild type [34]. Escape mutations can work through many mechanisms, including alteration of epitopes presented on HLA for T cell receptors, lack of antigen processing, absence of improper interaction with HLA and finally lack of recognition by T cell receptors. During HIV infection, selective pressure imposed by CTL leads to the generation of various escape mutations and these variants may constitute the majority of the total viral pool. It has been shown that the ratio of non-synonymous substitutions to synonymous substitutions was higher in the CTL epitope. This further confirms the role of CTL selection pressure for occurrence and then for maintenance of these mutations [35]. Later on, evidence of escape mutations in HLA-B8-restricted epitope in Nef, HLA-B44-restricted epitope in Env and HLA-B27-restricted Gag epitope KK10 have supported the CTL-mediated selection of these mutations [36]. Nef-mediated downregulation of major histocompatibility complex class I In addition to escape mutations, HIV has strategies that can make the infected cell undetectable by the immune system. The detection of any cell depends on cell surface markers and so effective strategies alter the organization and expression of such markers. To escape from CTL response, HIV inhibits surface expression of the host major histocompatibility complex (MHC) class I, which is most important for CTL recognition; this is achieved through a viral protein called Nef. HIV-1 Nef is a 27–34 kDa multifunctional protein that has no apparent enzymatic activity but functions as an adaptor protein that enters the cell membrane through amino-terminal myristoylation. Though the exact mechanism by which Nef disrupts MHC class I cell surface expression is not clear, the viral protein binds to the cytoplasmic tail of the class I protein and may disrupt class I trafficking [37]. The cytoplasmic domain of class I antigens has a highly conserved region of 33 amino acid residues with nine conserved serine residues; Nef protein interacts with this via amino-terminal α-helix, polyproline and acidic domains [38]. It was initially thought that Nef reduced MHC class I cell surface expression by accelerating endocytosis and promoting retrograde transport of internalized class I molecules to the trans-Golgi network (TGN) [39]. Nef protein can interact with phosphofurin acidic cluster sorting protein 1 and then can activate phosphatidylinositol 3-kinase [40], guanine exchange factor ARNO and finally ADP ribosylation factor 6 [41]. This pathway leads to internalization of MHC class I molecules to ‘ADP ribosylation factor compartments’ that finally reach the TGN. However, more recent work has shown that Nef disrupts transport of MHC class I in the secretory pathway to the cell surface, rather than causing endocytosis from the cell surface. Further, it has been demonstrated that adaptor protein 1 (AP-1) is necessary for Nef to disrupt class I trafficking [42]. The main function of AP-1 is to sort proteins at the TGN by binding their cytoplasmic tails to clathrin and directing them to endolysosomal pathways [43]. Nef-mediated disruption of class I surface expression may occur by allowing interaction between the cytoplasmic tail of an MHC class I molecule and AP-1, thus redirecting the molecules from the TGN to the lysosomes for degradation [42] as shown in Fig. 1. Recent work by Kasper et al.[44] has shown that Nef targets MHC class I in T cells early in the biosynthetic pathway by preferentially binding newly synthesized hypophosphorylated class I molecules. The preferential interaction of Nef prevents phosphorylation of these molecules and so also prevents them reaching the cell surface In summary, the work of Collins and coworkers [42,44] has demonstrated that Nef preferentially binds hypophosphorylated class I molecules, thus preventing completion of the secretory pathway that would finally provide an antigen-presenting receptor on the cell surface to activate killing of the virus-infected cell. Transport of class I molecules from the cell surface to the TGN occurs normally in infected cells but the class I molecules are then diverted to lysosomes through Nef-assisted binding of AP-1 to their cytoplasmic tail; this further inhibits their phosphorylation as well as their surface expression.Fig. 1: Probable mechanism of viral HIV-negative effector (Nef)-mediated major histocompatibility complex class I internalization that may fail with human leukocyte antigen (HLA) G. Nef and adaptor protein (AP) 1 interact with the cytoplasmic domain of the class I in the trans-Golgi network (TGN) and then redirect class I protein-containing vesicles to the endolysosomal pathway. The truncated cytoplasmic domain of HLA-G makes Nef-mediated recycling ineffective as Nef proteins cannot dock on HLA-G and so surface expression of HLA-G does not change during HIV infection.HLA genotype and cytotoxic T cells The HLA antigens activate cellular responses by forming the antigen-presenting component on the cell surface that interacts with CTL, directs them against the infected cells and activates natural killer (NK) cells of the innate immune response by interacting with the killer cell immunoglobulin-like receptor (KIR) family of surface molecules. There is substantial evidence that immune responses are effective in challenging the infection and transmission of HIV disease. Though various genetic factors have been associated with susceptibility to HIV (Table 1), investigations of the role of HLA antigens has concentrated on three areas: zygosity of HLA loci, sharing of alleles, and specific HLA allelic/haplotypic association with the outcome of disease. It has been shown that homozygosity at the class I loci is associated with relatively rapid progression to disease compared with heterozygotes [54]. This heterozygote advantage probably stems from the ability of such individuals to present a wider array of virus-derived epitopes to a more diverse CTL repertoire. This heterozygous repertoire will not only enable recognition and destruction of a greater breadth of infectious agents but will also require many more escape mutations for effective avoidance of the CTL response. Hence, heterozygosity may be associated with delayed progression to AIDS [50]. However, it is also conceivable that virus may become adapted and resistant to highly frequent alleles more easily in that population, and so a rare allele may have selective advantage in HIV disease progression [55]. The rare allele selective advantage may work in conjunction with heterozygote advantage, as the protective rare alleles are more likely to be present as heterozygotes.Table 1: Various genetic factors in HIV susceptibility.Another genetic component that predisposes to the progression of AIDS is HLA sharing. Where the MHC class I is common to the donor and recipient, the basis of successful transplantation, it would lead to increased susceptibility to viral infection. One natural model of viral transmission between HLA-sharing donor and recipient is mother-to-child transmission, which further supports increased transmission of HIV in these circumstances [56]. Further, significant increase in susceptibility to HIV has been shown to be associated with concordance at the HLA-B locus but not at HLA-A or HLA-C [57]. Knowing that a certain viral escape mechanism is likely to develop under a particular genetic selection pressure, it can be anticipated that an escape variant well adapted to a particular genetic profile and then transmitted to a host of similar genetic set up would be able to escape immunological challenges in the new host also. This may be a mechanism for susceptibility to viral transmission in hosts with HLA alleles in common. By comparison, MHC class I disparity may induce anti-HLA antibodies on passage of the virus and so may prevent HIV infection at early stages. Such a defence would be lacking in HLA concordant individuals, increasing successful transmission of HIV virus. Previous research in genetic predisposition to viral susceptibility in the context of HLA has concentrated on specific alleles. Various studies have confirmed the contribution of specific class I alleles and more particularly HLA-B alleles in the outcome of disease [58]. This remarkable contribution of HLA-B may be because this group has the highest diversity among the class I antigens: approximately 661 alleles compared with 372 in HLA-A and 190 alleles in HLA-C [59]. Further, substantially greater selection pressure would be imposed on HIV by HLA-B compared with other class I antigens. Consistent association with delayed disease progression has been seen with HLA-B*27 and HLA-B*57 [51]. Though the HIV HLA-B*57-specific epitope may an escape under selective pressure, this may cost in terms of viral fitness as the virus transmission to a new host has been as the class I susceptibility allele for AIDS heterozygotes have a rapid progression to and as as The most of are seen with its and which have at of their loaded and at By comparison, at does not have any substantial on disease can induce a CTL response, viral load was by and compared with It be that epitope recognition by and will induce CTL that may not function against cells. Some HLA-B alleles have been shown to the outcome of disease progression by interacting with on cells. The of the of various alleles may interact with of cells, thus of and disease progression have also been to particular MHC class but no have been One recent the in viral during of HLA-G and in progression of HIV disease the of mechanisms by HIV to the human immune response is with the expression of HLA antigens. 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