Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope

Abstract

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8 ؉ T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P ‫؍‬ 2 ؋ 10 ؊5 ). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ϳ90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8 ؉ T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8 ؉ T-cell response in all individuals, irrespective of HLA type.

HIV Subtype Influences HLA-B*07:02-Associated HIV Disease Outcome

“…This outcome hinges on a specific CD8 + T cell response to a single Gag epitope only available in C-clade infection. 27 Similarly, we observed that HLA alleles belonging to the B*07 superfamily, including HLA-B*07:02, were associated with disease progression in B-clade infection, but not in C-clade infection. Consistent with these findings, recent studies of 3,622 B-cladeinfected study subjects found that HLA-B*07:02 was associated with disease progression, 3,28 but this was not the case in a large cohort of 1,210 C-clade-infected individuals from Durban, South Africa.…”

“…6,[36][37][38] In contrast, several studies have consistently shown a strong independent effect of HLA-B*07:02 on disease progression in B-clade infection, 3,26,28 but not in C-clade infection, 6,27 and therefore suggest a consistent impact of HIV clade on the association of HLA-B*07:02 with rapid HIV disease progression.…”

Frequent and Variable Cytotoxic-T-Lymphocyte Escape-Associated Fitness Costs in the Human Immunodeficiency Virus Type 1 Subtype B Gag Proteins

“…However, 3 of the 29 mutations (A81T, D260E, and D312E; susceptible amino acid listed first, escape variant listed last) were atypical in that the identified escape mutation was actually the amino acid residue most frequently expressed by circulating HIV-1B viruses, i.e., the consensus amino acid. Such "negatope" escape mutations may be indicative of historically targeted CTL epitopes for which continuous CTL selection pressure resulted in the accumulation over time of the escape mutation to high frequency, resulting in an epitope that is "preescaped" in the majority of circulating viruses (27,57,58). The construction of NL4-3-derived recombinant viruses expressing each of the 29 mutations individually provided the opportunity to comprehensively quantify the fitness cost of HIV-1 CTL escape in Gag without a priori focus on any particular HLA class I allele, CTL epitope, or Gag protein.…”

“…As a result, most contemporary HIV-1B infections of individuals expressing HLA-B*35 or -B*44 will consist of a transmitted virus that is already escaped in the NY10 or AW11 epitope, respectively, which may contribute to the lack of protective benefit associated with these alleles (10,13). Interestingly, Matthews et al recently reported that the HLA-B*3501 Gag NY10 epitope is intact and not a negatope (D260) in the HIV-1C consensus, that the resultant effective targeting of the NY10 epitope in the HIV-1C-infected population was the only significant difference in HLA-B*3501-restricted CTL responses observed between HIV-1B-and HIV-1C-infected cohorts, and that unlike in HIV-1B infections the HLA-B*3501 allele is not deleterious in populations infected with HIV-1C (58). Overall, these data highlight the idea that negatopes are likely to represent uniquely poor targets for CD8 ϩ T cell responses.…”

Correlates of T-cell–mediated viral control and phenotype of CD8+ T cells in HIV-2, a naturally contained human retroviral infection

“…Interestingly, HLA-B*3501 is associated with higher HIV-1 VLs and more rapid disease progression in HIV-1 clade B infection 28 but protective outcomes in clade C infection. 35 The difference appears to be the greater Gag-directed response in clade C-infected HLA-B*3501-positive subjects (specifically targeting the p24 epitope NPPIPVGDIY), 36 a situation seemingly paralleled in HIV-2 infection. Maintaining a substantial breadth of T-cell responses is considered important in HIV-1 control and is associated with greater polyfunctionality and virus inhibition.…”