title: Molecular mechanisms of HIV type 1 prophylaxis failure revealed by single-genome sequencing.
abstract: Trials of human immunodeficiency virus type 1 (HIV) pre- and postexposure prophylaxis show promise. Here, we describe a novel strategy for deciphering mechanisms of prophylaxis failure that could improve therapeutic outcomes. A healthcare worker began antiretroviral prophylaxis immediately after a high-risk needlestick injury but nonetheless became viremic 11 weeks later. Single-genome sequencing of plasma viral RNA identified 15 drug susceptible transmitted/founder HIV genomes responsible for productive infection. Sequences emanating from these genomes exhibited extremely low diversity, suggesting virus sequestration as opposed to low-level replication as the cause of breakthrough infection. Identification of transmitted/founder viruses allows for genome-wide assessment of molecular mechanisms of prophylaxis failure.
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Lily
authors.initials: L
authors.lastname: Blair
authors.forename: Yalu
authors.initials: Y
authors.lastname: Chen
authors.forename: Gerald
authors.initials: G
authors.lastname: Learn
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Bar
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016679:Genome, Viral; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny; D011292:Premedication; D012367:RNA, Viral; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral
keywords: HIV-1 transmission; multiple virus transmission; occupational exposure; post-exposure prophylaxis; single genome sequencing; virus sequestration
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