HIV-1 evolutionary dynamics under non-suppressive antiretroviral therapy

Abstract

AbstractProlonged virologic failure on 2nd-line protease inhibitor (PI) based ART without emergence of major protease mutations is well recognised and provides an opportunity to study within-host evolution in long-term viraemic individuals. Using next-generation sequencing and in silico haplotype reconstruction we analysed whole genome sequences from longitudinal plasma samples of eight chronically infected HIV-1 individuals failing 2nd-line regimens from the ANRS 12249 TasP trial. On non-suppressive ART, there were large fluctuations in synonymous and non-synonymous variant frequencies despite stable viraemia. Reconstructed haplotypes provided evidence for selective sweeps during periods of partial adherence, and viral haplotype competition during periods of low drug exposure. Drug resistance mutations in reverse transcriptase (RT) from earlier and current ART were used as markers of viral haplotypes in the reservoir and their distribution over time indicated recombination. We independently observed linkage disequilibrium decay, indicative of recombination. These data highlight dramatic changes in virus population structure that occur during stable viremia under non suppressive ART.