PMID- 25473042 OWN - NLM STAT- MEDLINE DCOM- 20150408 LR - 20220129 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 89 IP - 4 DP - 2015 Feb TI - Host genetic and viral determinants of HIV-1 RNA set point among HIV-1 seroconverters from sub-saharan Africa. PG - 2104-11 LID - 10.1128/JVI.01573-14 [doi] AB - We quantified the collective impact of source partner HIV-1 RNA levels, human leukocyte antigen (HLA) alleles, and innate responses through Toll-like receptor (TLR) alleles on the HIV-1 set point. Data came from HIV-1 seroconverters in African HIV-1 serodiscordant couple cohorts. Linear regression was used to determine associations with set point and R(2) to estimate variation explained by covariates. The strongest predictors of set point were HLA alleles (B*53:01, B*14:01, and B*27:03) and plasma HIV-1 levels of the transmitting partner, which explained 13% and 10% of variation in set point, respectively. HLA-A concordance between partners and TLR polymorphisms (TLR2 rs3804100 and TLR7 rs179012) also were associated with set point, explaining 6% and 5% of the variation, respectively. Overall, these factors and genital factors of the transmitter (i.e., male circumcision, bacterial vaginosis, and use of acyclovir) explained 46% of variation in set point. We found that both innate and adaptive immune responses, together with plasma HIV-1 levels of the transmitting partner, explain almost half of the variation in viral load set point. IMPORTANCE: After HIV-1 infection, uncontrolled virus replication leads to a rapid increase in HIV-1 concentrations. Once host immune responses develop, however, HIV-1 levels reach a peak and subsequently decline until they reach a stable level that may persist for years. This stable HIV-1 set point represents an equilibrium between the virus and host responses and is predictive of later disease progression and transmission potential. Understanding how host and virus factors interact to determine HIV-1 set point may elucidate novel mechanisms or biological pathways for treating HIV-1 infection. We identified host and virus factors that predict HIV-1 set point in people who recently acquired HIV-1, finding that both innate and adaptive immune responses, along with factors that likely influence HIV-1 virulence and inoculum, explain approximately 46% of the variation in HIV-1 set point. CI - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved. FAU - Mackelprang, Romel D AU - Mackelprang RD AD - Department of Global Health, University of Washington, Seattle, Washington, USA. FAU - Carrington, Mary AU - Carrington M AD - Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratories for Cancer Research, Frederick, Maryland, USA Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA. FAU - Thomas, Katherine K AU - Thomas KK AD - Department of Global Health, University of Washington, Seattle, Washington, USA. FAU - Hughes, James P AU - Hughes JP AD - Department of Biostatistics, University of Washington, Seattle, Washington, USA Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. FAU - Baeten, Jared M AU - Baeten JM AD - Department of Global Health, University of Washington, Seattle, Washington, USA Department of Epidemiology, University of Washington, Seattle, Washington, USA Department of Medicine, University of Washington, Seattle, Washington, USA. FAU - Wald, Anna AU - Wald A AD - Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Department of Epidemiology, University of Washington, Seattle, Washington, USA Department of Medicine, University of Washington, Seattle, Washington, USA Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA. FAU - Farquhar, Carey AU - Farquhar C AD - Department of Global Health, University of Washington, Seattle, Washington, USA Department of Epidemiology, University of Washington, Seattle, Washington, USA Department of Medicine, University of Washington, Seattle, Washington, USA. FAU - Fife, Kenneth AU - Fife K AD - Department of Medicine, Indiana University, Indianapolis, Indiana, USA Department of Microbiology and Immunology, Indiana University, Indianapolis, Indiana, USA Department of Pathology, Indiana University, Indianapolis, Indiana, USA. FAU - Campbell, Mary S AU - Campbell MS AD - Department of Medicine, University of Washington, Seattle, Washington, USA. FAU - Kapiga, Saida AU - Kapiga S AD - Mwanza Intervention Trials Unit, National Institute for Medical Research, Mwanza, Tanzania Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Gao, Xiaojiang AU - Gao X AD - Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratories for Cancer Research, Frederick, Maryland, USA. FAU - Mullins, James I AU - Mullins JI AD - Department of Medicine, University of Washington, Seattle, Washington, USA Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA Department of Microbiology, University of Washington, Seattle, Washington, USA. FAU - Lingappa, Jairam R AU - Lingappa JR AD - Department of Global Health, University of Washington, Seattle, Washington, USA Department of Medicine, University of Washington, Seattle, Washington, USA Department of Pediatrics, University of Washington, Seattle, Washington, USA lingappa@u.washington.edu. LA - eng GR - T32AI007140/AI/NIAID NIH HHS/United States GR - T32 AI007140/AI/NIAID NIH HHS/United States GR - AI073115/AI/NIAID NIH HHS/United States GR - P01 AI030731/AI/NIAID NIH HHS/United States GR - G0901756/MRC_/Medical Research Council/United Kingdom GR - R21 AI073115/AI/NIAID NIH HHS/United States GR - P30 AI027757/AI/NIAID NIH HHS/United States GR - HHSN261200800001C/RC/CCR NIH HHS/United States GR - HHSN261200800001E/CA/NCI NIH HHS/United States GR - AI27757/AI/NIAID NIH HHS/United States GR - P01 AI057005/AI/NIAID NIH HHS/United States GR - HHSN261200800001E/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141203 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (HLA Antigens) RN - 0 (RNA, Viral) SB - IM MH - Africa South of the Sahara MH - Cohort Studies MH - Disease Susceptibility MH - Female MH - HIV Infections/*immunology/transmission/*virology MH - HIV-1/*isolation & purification MH - HLA Antigens/*genetics MH - Humans MH - Male MH - RNA, Viral/*blood MH - *Viral Load PMC - PMC4338863 EDAT- 2014/12/05 06:00 MHDA- 2015/04/09 06:00 PMCR- 2015/08/15 CRDT- 2014/12/05 06:00 PHST- 2014/12/05 06:00 [entrez] PHST- 2014/12/05 06:00 [pubmed] PHST- 2015/04/09 06:00 [medline] PHST- 2015/08/15 00:00 [pmc-release] AID - JVI.01573-14 [pii] AID - 01573-14 [pii] AID - 10.1128/JVI.01573-14 [doi] PST - ppublish SO - J Virol. 2015 Feb;89(4):2104-11. doi: 10.1128/JVI.01573-14. Epub 2014 Dec 3.