Distinct host genetic determinants of HIV acquisition and disease progression: the case of classical HLA class I

HIV acquisition and disease progression appear to be influenced by largely distinct host genetic factors. Whether infection becomes established is determined shortly after mucosal or parenteral exposure, before HIV-specific CD8⁺ T-cell responses become detectable. Progression is shaped by immune responses acting after infection is established and is strongly influenced by classical HLA class I variation. CCR5Δ32 affects both phenotypes, raising the possibility of shared determinants, but evidence for genetic overlap remains limited. Here, we review evidence on whether classical HLA class I variation is associated with HIV acquisition across diverse exposure routes and study designs. A large collaborative genome-wide association study (GWAS) found no significant association between HLA class I variation and HIV acquisition after accounting for frailty bias, and candidate-gene associations have not been independently replicated. Future research should prioritize well-characterized exposure cohorts and sequencing approaches capable of detecting structural variation and resolving complex loci such as killer-cell immunoglobulin-like receptors (KIRs), particularly in underrepresented African populations.