title: 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.
authors: Department of Medicine, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL, 35294, USA.
authors: Xuelin
authors: X
authors: Li
authors: Matthew A
authors: MA
authors: Price
authors: Dongning
authors: D
authors: He
authors: Anatoli
authors: A
authors: Kamali
authors: Etienne
authors: E
authors: Karita
authors: Shabir
authors: S
authors: Lakhi
authors: Eduard J
authors: EJ
authors: Sanders
authors: Omu
authors: O
authors: Anzala
authors: Pauli N
authors: PN
authors: Amornkul
authors: Susan
authors: S
authors: Allen
authors: Eric
authors: E
authors: Hunter
authors: Richard A
authors: RA
authors: Kaslow
authors: Jill
authors: J
authors: Gilmour
authors: Jianming
authors: J
authors: Tang
mesh_terms: D000328:Adult; D000351:Africa, Eastern; D000354:Africa, Western; D000483:Alleles; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006679:HIV Seropositivity; D015497:HIV-1 / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D015236:HLA-C Antigens / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008297:Male; D015999:Multivariate Analysis; D019655:Quantitative Trait, Heritable; D012737:Sex Factors; D019562:Viral Load; D055815:Young Adult
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens