Additive Contribution of HLA Class I Alleles in the Immune Control of HIV-1 Infection

Abstract

Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.

Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

“…Even so, large cross-sectional studies have found that subjects whose CD8 + T cells preferentially target the structural protein Gag are more likely to sustain lower VL in chronic HIV-1 infection (9). The importance of epitope specificity to virus control is also suggested by genetic studies that found lower VL and delayed disease progression associated with the expression of certain HLA alleles, B*57/5801, B*27, B*51, and B*8101 (10)(11)(12), and the finding that protection is linked to the number of T cell responses restricted by these HLA types (13).…”

CD8 + T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

“…Of the 70 patients included in this study, 35 possessed protective HLA class I alleles (A*74:01, B*57, B*58:01, and B*81:01) (3,(13)(14)(15)(16)(17). These HLA alleles were selected as the principal protective alleles and are consistently the most protective that have been identified in the Durban study population (17,30,33). The HLAs that restricted responses seen in the nonprotective HLA group include HLAs B*15:10, B*08:01, B*44:03, B*14:02, B*42:01, B*45:01, B*39:10, and B*40:01 alleles.…”

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

“…While individually B57 plays a role with HIV-1 disease non-progression, it is unclear what the protective effects of multi-allelic polymorphisms are in individuals that carry more than one of these protective alleles. Leslie et al (2010) have recently demonstrated the power of additive effects of HLA-B class I alleles in a large cohort of HIV C-clade-infected individuals from South Africa (n51211). Even after excluding the alleles identified to have the strongest positive (B57 and B5801) and negative influence (B5802 and B18) on subject viral load and CD4 + T-cell count (P,0.0001).…”