The Majority of Currently Circulating Human Immunodeficiency Virus Type 1 Clade B Viruses Fail To Prime Cytotoxic T-Lymphocyte Responses against an Otherwise Immunodominant HLA-A2-Restricted Epitope: Implications for Vaccine Design

Abstract

Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr 59-67 ) that is targeted by acute-phase HIV-1-specific CD8 ؉ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I 60 L variant all developed these responses. The I 60 L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic Tlymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.The human immunodeficiency virus type 1 (HIV-1) epidemic is characterized by a high genetic diversity within the viral population that results from high replication and mutation rates in the presence of immunological selection pressure (29). Viral strains from the same HIV-1 clade can differ by 25% at the amino acid level, depending on the particular HIV-1 protein under consideration (29). This substantial sequence diversity poses a major challenge to the design of vaccines capable of inducing cross-reactive CD8 ϩ T-cell responses. As a consequence, the use of clade-specific consensus sequences has been recently proposed for vaccine design (12). Clade consensus sequences have the advantage of being most similar to currently circulating strains of interest, with each amino acid corresponding to the most commonly found amino acid at that position within the overall viral population.A number of studies have demonstrated that HIV-1 can rapidly escape from CD8 ϩ T-cell-mediated immune pressure by sequence variation within or flanking targeted epitopes (1,6,11,14,15,18,20,(23)(24)(25). The accumulation of escape variants within epitopes presented by the HLA class I alleles expressed in an infected individual can result in "HLA footprints" on the viral sequence (21,22,30). Recent data demonstrate that these cytotoxic T-lymphocyte (CTL) escape variants can be transmitted and impair the generation of otherwise immunodominant immune responses during primary infection in a new host (1,14,20). The rate at which these sequence mutations within epitopes may accumulate in the viral population largely depends on ...

Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol

“…A different pattern of changing epitopic usage over time is illustrated by responses to the immunodominant HLA-A2-restricted Gag 77-85 ( 77 SLYNTV ATL 85 [SL9]) epitope in p17 Gag. SL9 is recognized by the majority of chronically infected individuals but not by most acutely infected individuals (4,10,16,18,21,24,37). This temporal relationship for CTL recognition of virus proteins/ epitopes is also supported by observations that the HIV-1-Nef protein is recognized before other proteins (2,5,9,28) and, in mouse models, by constantly evolving CTL immunodominance (7,(42)(43)(44).…”

“…Using the intracellular cytokine flow cytometry (ICS) assay (23,24), only 3 of 20 patients had a detectable CTL response measured by the production of interferon gamma (IFN-␥) against the SL9 epitope. Prior studies have repeatedly shown responses to the SL9 epitope in the majority of chronically infected, antiretroviral-untreated subjects (4,18,21,22,37), although these responses were not always immunodominant (8).…”

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…Although reduced infection risk with possession of the HLA-A2 supertype was reported for two Nairobi cohorts (17), HLA-A2-restricted CTL responses to clade B virus infection do not appear to suppress virus effectively in infected individuals (18 -20). This has led to the suggestion that useful HLA-A2-restricted epitopes in circulating clade B viruses may have been lost because the clade B epidemic is historically older than the clade C epidemic and HLA-A2 is more prevalent in the West than in Africa (19,20). Loss of epitopes restricted by MHC alleles with high frequencies was also supported by studies in HIV-1 clade C-infected cohorts (21,22) and in SIV-infected macaques (23).…”

“…HLA typing was possible for 280 of these samples, of which 121 were HLA-A2 ϩ . OLP21 (PRTLNAWVKVVEEKAP, p24 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] ) was recognized by 24 subjects, with most of this reactivity (14 of 24) likely directed against the HLA-B*1503-restricted VKV VEEKAF epitope frequently seen in HLA-B*1503-expressing subjects (21). Reactivity to the nonameric TV9 peptide was confirmed in one of two HLA-A2 ϩ HLA-B*1503 Ϫ samples tested that reacted to OLP21 (L8 47, 500 sfc/10 6 PBMCs; Fig.…”

HLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1

“…In contrast, A*02 and B*07 were associated with higher VRC (0.948 versus 0.816 for A*02 and 0.987 versus 0.831, q ϭ 0.175, respectively [ Table 1]). The fact that these alleles are both common in the U.S. population (A*02 frequency, 28.3% for Caucasians and 18.7% for African Americans; B*07 frequency, 11.3% for Caucasians and 9.8% for African Americans) (12) suggests the possibility that these are not actively increasing VRC but rather that the virus may have become most adapted to these populations, rendering them neutral in comparison to a large group of less-frequent HLA alleles, which may still be impacting viral load (1,20,29).…”