Immunogenetic determinants of heterosexual HIV-1 transmission: key findings and lessons from two distinct African cohorts.

Immunogenetic studies in the past three decades have uncovered a broad range of human genetic factors that seem to influence heterosexual HIV-1 transmission in one way or another. In our own work that jointly evaluated both genetic and nongenetic factors in two African cohorts of cohabiting, HIV-1-discordant couples (donor and recipient pairs) at risk of transmission during quarterly follow-up intervals, relatively consistent findings have been seen with three loci (IL19, HLA-A, and HLA-B), although the effect size (i.e., odds ratio or hazards ratio) of each specific variant was quite modest. These studies offered two critical lessons that should benefit future research on sexually transmitted infections. First, in donor partners, immunogenetic factors (e.g., HLA-B57 and HLA-A36:01) that operate directly through HIV-1 viral load or indirectly through genital coinfections are equally important. Second, thousands of single-nucleotide polymorphisms previously recognized as "causal" factors for human autoimmune disorders did not appear to make much difference, which is somewhat puzzling as these variants are predicted or known to influence the expression of many immune response genes. Replicating these observations in additional cohorts is no longer feasible as the field has shifted its focus to early diagnosis, universal treatment, and active management of comorbidities.