title: Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 prevention clinical trial.
abstract: BACKGROUND
  Characterization of viruses in HIV-1 transmission pairs will help identify biological determinants of infectiousness and evaluate candidate interventions to reduce transmission. Although HIV-1 sequencing is frequently used to substantiate linkage between newly HIV-1 infected individuals and their sexual partners in epidemiologic and forensic studies, viral sequencing is seldom applied in HIV-1 prevention trials. The Partners in Prevention HSV/HIV Transmission Study (ClinicalTrials.gov #NCT00194519) was a prospective randomized placebo-controlled trial that enrolled serodiscordant heterosexual couples to determine the efficacy of genital herpes suppression in reducing HIV-1 transmission; as part of the study analysis, HIV-1 sequences were examined for genetic linkage between seroconverters and their enrolled partners.
  
  
  RESULTS
  We obtained partial consensus HIV-1 env and gag sequences from blood plasma for 151 transmission pairs and performed deep sequencing of env in some cases. We analyzed sequences with phylogenetic techniques and developed a Bayesian algorithm to evaluate the probability of linkage. For linkage, we required monophyletic clustering between enrolled partners' sequences and a Bayesian posterior probability of ≥ 50%. Adjudicators classified each seroconversion, finding 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) indeterminate transmissions, with linkage determined by consensus env sequencing in 91 (84%). Male seroconverters had a higher frequency of unlinked transmissions than female seroconverters. The likelihood of transmission from the enrolled partner was related to time on study, with increasing numbers of unlinked transmissions occurring after longer observation periods. Finally, baseline viral load was found to be significantly higher among linked transmitters.
  
  
  CONCLUSIONS
  In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Campbell
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: James P
authors.initials: JP
authors.lastname: Hughes
authors.forename: Connie
authors.initials: C
authors.lastname: Celum
authors.forename: Kim G
authors.initials: KG
authors.lastname: Wong
authors.forename: Dana N
authors.initials: DN
authors.lastname: Raugi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sorensen
authors.forename: Julia N
authors.initials: JN
authors.lastname: Stoddard
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Wenjie
authors.initials: W
authors.lastname: Deng
authors.forename: Erin
authors.initials: E
authors.lastname: Kahle
authors.forename: Dana
authors.initials: D
authors.lastname: Panteleeff
authors.forename: Jared M
authors.initials: JM
authors.lastname: Baeten
authors.forename: Francine E
authors.initials: FE
authors.lastname: McCutchan
authors.forename: Jan
authors.initials: J
authors.lastname: Albert
authors.forename: Thomas
authors.initials: T
authors.lastname: Leitner
authors.forename: Anna
authors.initials: A
authors.lastname: Wald
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: Jairam R
authors.initials: JR
authors.lastname: Lingappa
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D003710:Demography; D005260:Female; D008040:Genetic Linkage; D006679:HIV Seropositivity / Q000453:epidemiology / Q000235:genetics* / Q000635:transmission / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008297:Male; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D012747:Sexual Partners; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus