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

Tripathi, Piyush; Agrawal, Suraksha

doi: 10.1097/QAD.0b013e32810c8bbc
Editorial Review

From the Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow (UP) 226014, India.

Received 22 September, 2006

Revised 29 January, 2007

Accepted 14 February, 2007

Correspondence to Professor Suraksha Agrawal, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow (UP) 226014, India. E-mail:

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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.

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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.

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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].

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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

Fig. 1

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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

Table 1

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 ‘TW 10’ may undergo an escape mutation, T242N, under selective pressure, this may cost in terms of viral fitness as the virus reverts after transmission to a new host [60]. Another allele, HLA-B*35, has been implicated as the class I susceptibility allele for AIDS [52]. HLA-B*35 heterozygotes have a rapid progression to AIDS, and homozygotes progress twice as fast as HLA-B*35-negative individuals. The most deleterious effects of HLA-B*35 are seen with its two subtypes, HLA-B*3502 and B*3503, which have proline at anchor position 2 of their loaded peptide and non-tyrosine residue at position 9 [52]. By comparison, HLA-B*3501 containing tyrosine at position 9 does not have any substantial effect on disease prognosis. While both HLA-B*35 subtypes can equally induce a CTL response, viral load was cleared less effectively by non-tyrosine-containing HLA-B*3502 and B*3503 compared with HLA-B*3501 [61]. It may, therefore, be possible that altered epitope recognition by HLA-B*3502 and B*3503 will induce CTL that may not specifically function against HIV-1-infected cells.

Some HLA-B alleles have been shown to influence the outcome of disease progression by interacting with KIR on NK cells. The Bw4 motif (residues 79–84 of the α3 domain) of various HLA-Bw4 alleles may interact with activating receptors KIR3DS1 of NK cells, thus facilitating clearance of HIV-1-infected lymphocytes and slowing disease progression [62].

Studies have also been performed to examine particular MHC class II genes, but no consistent effects have been revealed. One recent study implicated the DRβ1*13–DQβ1*06 haplotype in viral suppression during treatment [63].

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Role of HLA-G and HLA-E in progression of HIV disease

Among the myriad of mechanisms adopted by HIV to avoid the human immune response is interference with the expression of HLA antigens. One evasion strategy is to downregulate cell surface class I classical antigens (HLA-A and HLA-B) to avoid HIV-specific CTL responses. Normally any change in the self HLA profile of cells is easily detected by immune surveillance and such cells are then subjected to degradation. However, despite reduced expression of class I antigens, HIV-infected cells are resistant to lysis by NK cells. During viraemic HIV-1 infection, there is expansion of an anergic subset of NK cells that do not respond to stimulation with MHC-devoid target cells. These NK cells have increased expression of SHIP (SH2-containing inositol phosphatase), which may be responsible for the reduced functional activity of these cells in chronic HIV-1 infection [64]. Various NK cell receptors that recognize MHC-independent ligands can regulate key cytolytic NK functions. A recent study has demonstrated that these inhibitory receptors recognizing an MHC-independent ligand are overexpressed in SHIP knockout mice and, therefore, may regulate NK cell cytolytic activity. This would suggest that SHIP plays an important role in regulation of this MHC-independent inhibitory NK receptor repertoire, which, in turn, is crucial for NK recognition and cytolysis of various targets [65]. However, this immunoprotection could also be achieved by increased expression of HLA-G and HLA-E during HIV infection. These antigens are less polymorphic than their classical counterparts. Where HIV Nef downregulates surface class I antigens by interacting with their cytoplasmic domain [66], it may not be able to interact with non-classical HLA-I antigens such as HLA-G, which has a truncated domain [67] (Fig. 1). Apart from any effects of the shorter cytoplasmic tail in HLA-G, it has been speculated that various mechanisms may upregulate HLA-G and HLA-E. The impact of these non-classical class I antigens on susceptibility to HIV infection is supported by their immunoregulating properties (Fig. 2).

Fig. 2

Fig. 2

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HIV and HLA-G with a truncated cytoplasmic domain

HLA G was cloned by Geraghty et al. in 1987 [67]. It is less polymorphic, as only 15 alleles are known to date. It has restricted tissue distribution compared with the classical class I antigens. Though initially HLA-G was implicated in the maintenance of tolerance during pregnancy, its role has been explored in the tumour escape mechanism in various cancers and also in organ transplantation.

The exon organization of HLA-G is similar to the classical class I molecules, with three external domains (α1, α2, α3), a transmembrane domain and a cytoplasmic domain, and it is associated with β2-microglobulin to make the complete structure [68]. But HLA-G is more peculiar as it possesses a premature stop codon in exon 6 that results in a truncated cytoplasmic tail (it translates 6 amino acids instead of 30) [67]. HLA-G exists in multiple isoforms, created by alternative splicing [69]. Seven different HLA-G transcriptional isoforms have been described; four of these encode membrane-bound forms whereas the remaining three encode soluble isoforms. HLA-G is identified as an immunoregulatory molecule as it can interact with inhibitory KIR of NK cells. So far, three HLA-G specific KIR have been identified: ILT-2 (LIR-1), ILT-4 (LIR-2) and KIR2DL4 (Table 2) [74,75]. In addition to acting via the innate mechanisms, HLA-G also provides protection through acquired immunity. HLA-G5 induces apoptosis of activated CD8 cells through activation of the Fas/FasL pathway [76] whereas HLA-G1 suppresses CD4 lymphocyte proliferation [77]. Interaction of HLA-G1 with KIR of T cells can inhibit the antigen-specific HLA-restricted CTL response [76], thus confirming the functionality of HLA-G in protecting cells from all possible immune responses.

Table 2

Table 2

HIV infection is characterized by loss of HLA-A and HLA-B, but the expression of HLA-G remains unaffected or at least not decreased. Along with inability of viral Nef to downregulate HLA-G, there could be some changes indirectly influencing the expression of HLA-G, particularly increased interleukin 10 [78]. It has been shown that this cytokine upregulates expression of HLA-G [79]. Lozano et al. [80] demonstrated the increased expression of HLA-G in all monocytes and some T lymphocytes after HIV infection. Other evidence had implicated HAART in upregulation of HLA-G [81], but the study by Lozano et al. [80] excluded this mechanism by showing elevated levels of HLA-G in untreated HIV-positive individuals. A contradictory report by Derrien et al. [82] showed downregulation of HLA-G in HIV infection. Though these authors agreed that this was an Nef-independent process, as HLA-G is unable to interact with Nef, they thought it was more likely to be a viral protein U (Vpu)-dependent mechanism as HLA-G possesses a dilysine motif (RKKSSD) at −4 and −5 from the carboxy-terminus [67] with which Vpu could interact and interfere with further intracellular trafficking of HLA-G. The difference between these two studies may arise for two reasons. First, Derrien et al. [82] studied expression in cell lines, which would have subtle differences in microenvironment from in vivo. Second, the stage of infection may have a profound effect on the microenvironment, which, in turn, could alter HLA-G expression. Derrien et al. [82] studied HLA-G expression in acute HIV infection, and their results are similar to other acute viral infections such as human cytomegalovirus and herpes simplex virus. These both decrease cell surface expression of HLA-G1, but the former particularly can increase HLA-G1 expression upon reactivation [83,84]. Possibly the expression of HLA-G could be enhanced in the natural course of HIV infection so that the situation in chronic infection would be as shown by Lozano et al. [80].

Further, HLA-G polymorphism is also associated with the risk of HIV infection. Matte et al. [85] carried out an extensive study of HLA-G polymorphism in 456 HIV-seropositive and 406 HIV-seronegative African women and found significant association of G*0105N with protection from HIV-1 infection and G*010108 with susceptibility to infection. Allele G*0105N is characterized by deletion of cytosine at position 130 of exon 3, leading to frameshift and introduction of a stop codon in exon 4 [86]. Hence allele G*0105N impedes production of a functional HLA-G molecule. The most likely reason for association of G*0105N with protection from HIV infection would be that this impairs the function of HLA-G and so downregulation by HIV would be absent or decreased. Recently Lajoie et al. [53] presented more extended and explicit data for HLA-G polymorphism in the same cohort. They found that women carrying G*0105N had a 2.2-fold decreased risk of HIV-1 infection compared with women without G*0105N. They also reported an HIV- seronegative woman who was homozygous for G*0105N.

The G*010108 allele, reported to be associated with increased risk of HIV-1 infection [85], has a synonymous substitution (proline) of G to A at codon 57. Though this mutation does not bring about any change in amino acid sequence, it is in the vicinity of Glu-63, which interacts with the P2 position of loaded peptide [87]. In the mouse homologue Qa-2, P1 arginine of the peptide interacts with Glu-62, Glu-63, Tyr-59 and Trp-167 residues, three out of four of which are in close proximity to Pro-57. Another HLA-G allele, G*010401, shares variation at codon 57 with G*010108, although it also has a non-synonymous substitution at codon 110. The G*010108/G*010401 genotype has been shown to have a greater association with increased risk of HIV infection [85]. However, this may be because G*010401 is a high secretor allele associated with increased secretion of soluble HLA-G molecules, consequently being open to more systemic downregulation. All individuals identified with G*010108/G*010401 were homozygous at codon 57 [85]. Though this position is not directly involved in the presentation of peptide, zygosity of HLA at this position could still affect susceptibility to HIV infection. Aikhionbare et al. [88] have shown that discordance at codon 57 of HLA-G exon 2 was significantly associated with non-transmission of HIV-1 infection in mother–child pairs studied to investigate the risk of perinatal HIV transmission. This is probably in agreement with the observations discussed above that HLA sharing leads to increased susceptibility to HIV-1 transmission. However, more studies are needed to validate these observations, particularly for HLA-G.

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HIV and the less polymorphic HLA-E

HLA-E was initially recognized as HLA-6.2 and was mapped to chromosome 6p21.3 between HLA-C and HLA-A [89]. HLA-E has a wide tissue distribution including T cells, B cells, activated T lymphocytes and various other cells such as placenta cells and trophoblasts [90,91]. HLA-E is less polymorphic, having only three alleles identified so far. These three alleles can be differentiated as HLA-ER (0101) and HLA-EG (01031 and 01032) by a non-synonymous substitution of arginine by glycine at position 107. Alleles 01031 and 01032 differ only by a synonymous mutation at codon 77.

HLA-E also has NK-regulating properties, as HLA-E has been identified as a ligand of a subset of the immunoglobulin superfamily of NK cell receptors, and their interaction with KIR of NK cells may be responsible for inhibition of killer activities in these cells [92]. HLA-E is distinct in that it depends for surface expression on a highly conserved nonamer peptide derived from the signal sequence of other class I molecules including HLA-A, HLA-B, HLA-C and HLA-G, but not HLA-F [93]. The peptide structure is very important, as only appropriate peptide can be loaded onto HLA-E, enabling expression and subsequent protection of target cells by interaction of the HLA-E–peptide complex with the CD94/NKG2 receptor of NK cells [94].

A potential role for HLA-E in susceptibility to HIV has been neglected until a recent report showed that it was upregulation during p24-positive HIV-1 infection [95]. Though HLA-E has wide tissue distribution, its dependency on peptides derived from MHC class I may affect its expression on HIV-1-infected cells, as they have decreased class I expression. However, HLA-E expression could be supported by peptides derived from HLA-G or of viral origin. There is evidence of HLA-E upregulation by viral peptides: UL40-derived peptide in human cytomegalovirus [96] and core 35–45 peptide in herpes simplex virus [97]. It has also been shown that HLA-E is upregulated by peptide 14–22 derived from HIV p24. Comparison of the HIV p2414–22 peptide with the sequences of other known HLA-E-specific peptides showed that it was very similar, with only subtle changes, and matched the HLA-E-binding criteria. HIV p2414–22 shares isolucine at position 2, which appears to be essential for HLA-E interactions, and has residues at positions 4, 6 and 7 that are similar to those identified in other HLA-E-specific peptides. HIV p2414–22 peptide has asparagine at position 5, which may be essential for HLA-E–peptide complex interaction with CD94/NKG2A, an HLA-E-specific inhibitory NK cell receptor. It has been reported that upregulation of HLA-E by HIV p2414–22 can inhibit cytolytic function of NK cells by interacting particularly with inhibitory CD94/NKG2A receptor.

Specificity of this HLA-E–peptide complex interaction with CD94/NKG2A, responsible for inhibition of NK cell cytolysis, was further confirmed by studies that restored NK cell cytolytic activity by blocking HLA-E with specific monoclonal antibody 3D12 or blocking CD94/NKG2A with specific anti-NKG2A antibody [98]. The HLA-E-specific HIV p2414–22 peptide is derived from HIV Gag, and as it consists of a putative proteasome cleavage site, it is conceivable that the peptide could be processed by proteasomal cleavage during natural HIV infection.

There are reports relating to HLA-E polymorphism with susceptibility to HIV-1 infection. Lajoie et al. [53] have demonstrated association of HLA-EG allele with protection against HIV infection. HLA-EG is known to have better immunoregulating properties than HLA-ER. HLA-EG has also been associated with other pathologies, for example nasopharyngeal carcinoma [98] and affected pregnancy outcome [99]. Strong et al. [94] have shown that HLA-EG–peptide complex always has higher surface expression than the HLA-ER–peptide complex and HLA-EG is also more thermally stable. When affinity with peptides of various origins was tested, it was found that the relative affinity of HLA-EG for peptide was significantly higher than that of HLA-ER [94].

As there is substantial evidence for a role for HLA-EG in efficient immunoregulation, its association with better prognosis in HIV infection would be expected; yet the converse is observed, which further suggests that, under cellular stress, HLA-E upregulation instead of immunoprotection supports immunosurveillance. HLA-E can interact with the leader peptide derived from heat shock protein 60 (hsp60) [100], which is generated in response to cellular stress. However, presentation of hsp60-derived peptide on HLA-E would not be sufficient to inhibit NK cell cytolytic activity, as the HLA-E–peptide complex could not interact efficiently with CD94/NKG2A [100]. The same situation might also occur with the HIV-derived peptide. As KIR receptors specifically identify HLA-E complexed with cellular peptide in order to stimulate NK cell inhibition, complexes with non-cellular peptides might interfere with this recognition by the inhibitory receptor. Further HLA-EG has higher stability and affinity with peptide than HLA-ER [94], hence it may have a more rigid three-dimensional conformation – and even subtle changes could be identified by CD94/NKG2A. There is also the possibility that HLA-E could induce virus-specific CTL immune responses, as in the case of cytomegalovirus-derived peptide. However, these assumptions require extensive functional studies to validate the impact of HLA-E and HIV-derived peptide on NK cell receptors.

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                    HLA; MHC class I; HIV; immune response; escape mutation

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