Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions

Abstract

Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of “missing heritability” in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.

Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

“…Second, despite their narrow ranges, log 10 -transformed CD8 counts are informative quantitative traits for various statistical modeling, as multiple factors associated with CD8 counts can be established. Third, HLA variants (A*03:01, B*15:10, and B*58:02) associated with CD8 counts have little or no overlap with those (e.g., B*18, B*45, B*53, B*57, and B*81) previously reported for VL and CD4 counts in the same study cohort (32,33,47), suggesting that the underlying mechanisms should be distinct and may even precede HIV-1 infection (i.e., through intrinsic functions). Analyses of similar data from other cohorts should facilitate a better understanding of CD8 T-cell function in HIV-1 infection and in general populations (45).…”

“…starkly from those of two other commonly studied outcomes, i.e., the HIV-1 VL and CD4 T-cell counts. First, unlike the VL and CD4 counts, which often differ by sex and geography (a proxy for viral subtypes) (32,33,47), CD8 counts and their trajectories during primary HIV-1 infection are similar between men and women and between eastern and southern Africans, which can substantially simplify the search for generalizable and biological correlates using aggregated (instead of stratified) data (47). Second, despite their narrow ranges, log 10 -transformed CD8 counts are informative quantitative traits for various statistical modeling, as multiple factors associated with CD8 counts can be established.…”

Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort

“…Our statistical analysis identified infection by subtype C viruses and HLA-A*03 genotype to be associated with neutralization breadth. However, the relatively low significance of these associations in our multivariate analysis suggests that the correlation may be essentially due to the impact of these parameters on viral load itself [ 28 , 60 ]. Nevertheless, particular phenotypic and genotypic features of subtype C transmitted/founder viruses have been described that could potentially favor the development of neutralization breadth [ 61 – 64 ].…”

Human genetic variation in HIV disease

“…Proposed mechanisms include socioeconomic differences between HIV infected men and women, a direct effect of sex hormones and X chromosomal variation (reviewed in [21]). In a study of 521 recent seroconverters from eastern and southern Africa, Li et al [12] examined the potential impact on viral load of interactions between HLA genes and sex during primary infection. They observed a significant interaction for HLA AÃ03 : 01, with a strong reduction in VL among female carriers but not male.…”