Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1

Abstract

The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8⁺cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log₁₀VL among those with HLA allele B*57 (P= 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P= 0.002 to 0.016); the same analyses also demonstrated higher log₁₀VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P= 0.010 to 0.033). These HLA effects remained strong (P= 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P= 0.001 to 0.084). In contrast, neither B*35 (n= 15) nor B*53 (n= 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.