title: Host genetic and viral determinants of HIV-1 RNA set point among HIV-1 seroconverters from sub-saharan Africa.
abstract: 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.
  
  
  OBJECTIVE
  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 ∼46% of the variation in HIV-1 set point.
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Romel D
authors.initials: RD
authors.lastname: Mackelprang
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Thomas
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, USA Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Hughes
authors.affiliation: 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.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Baeten
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Wald
authors.affiliation: 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.
authors.forename: Carey
authors.initials: C
authors.lastname: Farquhar
authors.affiliation: 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.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fife
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Campbell
authors.affiliation: 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.
authors.forename: Saida
authors.initials: S
authors.lastname: Kapiga
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratories for Cancer Research, Frederick, Maryland, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: 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.
authors.forename: Jairam R
authors.initials: JR
authors.lastname: Lingappa
mesh_terms: D017954:Africa South of the Sahara; D015331:Cohort Studies; D004198:Disease Susceptibility; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000302:isolation & purification*; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D012367:RNA, Viral / Q000097:blood*; D019562:Viral Load
chemical_list: D006680:HLA Antigens; D012367:RNA, Viral