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

• Type of Material: Article
• Authors: Xuelin Li, University of Alabama Birmingham; Matthew A. Price, International AIDS Vaccine Initiative; Dongning He, University of Alabama Birmingham; Anatoli Kamali, MRC/UVRI Uganda Virus Research Unit on AIDS; Etienne Karita, Projet San Francisco; Shabir Lakhi, Emory University; Eduard J. Sanders, Kenya Medical Research Institute (KEMRI); Omu Anzala, Kenya AIDS Vaccine Initiative (KAVI); Pauli N. Amornkul, International AIDS Vaccine Initiative; Susan Allen, Emory University; Eric Hunter, Emory University; Richard A. Kaslow, International AIDS Vaccine Initiative; Jill Gilmour, Chelsea & Westminster Hospital; Jianming Tang, University of Alabama Birmingham
• Language: English
• Date: 2014-09-01
• Publisher: Springer International Publishing AG
• Publication Version: Final Published Version
• Copyright Statement: © 2014, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00439-014-1465-x
• Title of Journal or Parent Work: Human Genetics
• ISSN: 0340-6717
• Volume: 133
• Issue: 9
• Start Page: 1187
• End Page: 1197
• Grant/Funding Information: This work was funded in part by IAVI and made possible by the support from many donors, including: the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID).; The full list of IAVI donors is available at http://www.iavi.org; Additional funding for this work came from (i) the United States National Institute of Allergy and Infectious Diseases (NIAID), through two R01 grants (AI071906 to R.A.K./J.T. and AI064060 to E.H.), (ii) the Fogarty AIDS International Training and Research Program (AITRP) (grant FIC 2D43 TW001042 to S.L.), and (iii) the KEMRI-Wellcome Trust Research Programme at the Centre for Geographical Medicine Research-Kilifi (Wellcome Trust award #077092).
• Keywords: Genetics & Heredity; QUANTITATIVE TRAITS; EXTENDED HUMAN MHC; Science & Technology; GENETICS & HEREDITY; DISEASE PROGRESSION; LEUKOCYTE ANTIGENS; Life Sciences & Biomedicine; MISSING HERITABILITY; HEREDITARY HEMOCHROMATOSIS; T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS TYPE-1; HLA CLASS-I; HETEROSEXUAL TRANSMISSION
• Research Categories: Health Sciences, Public Health; Health Sciences, Epidemiology

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.