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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.

Original publication




Journal article


J Infect Dis

Publication Date





1598 - 1603


HIV-1 transmission, multiple virus transmission, occupational exposure, post-exposure prophylaxis, single genome sequencing, virus sequestration, Anti-HIV Agents, Drug Resistance, Viral, Female, Genome, Viral, HIV Infections, HIV-1, Humans, Middle Aged, Mutation, Phylogeny, Premedication, RNA, Viral, Sequence Analysis, DNA, Treatment Failure