Higher Selection Pressure from Antiretroviral Drugs in Vivo Results in Increased Evolutionary Distance in HIV-1 pol

Abstract

We investigated the effect of selection pressures on evolution of HIV-1 pol in 51 patients after switching to a new antiretroviral combination reverse transcriptase (RT) inhibitor therapy. Evolution of the protease (PR) and RT reading frames were analysed separately. Pairwise evolutionary distances (ED) were calculated between sequences from baseline and week 8 and between baseline and week 48 of protocol therapy. ED were calculated for all substitutions and for synonymous and nonsynonymous substitutions separately. At week 8 when HIV RNA reduction (selection pressure) was high, significantly more divergence in pol in both synonymous and nonsynonymous substitutions was found in patients with substantial RNA reduction (strong responders). Separate analyses of PR and RT revealed significantly greater ED in the RT (under selection pressure) of strong compared with nonresponders, whereas divergence between PR genes (not under selection pressure) did not differ in those two groups. Such differential evolution indicates that PR and RT were genetically unlinked and suggests recombination. The rapid increase of ED over the first 8 weeks was followed by only a minimal further rise by week 48, suggesting that selection of preexisting quasispecies accounted for the early changes. A disproportionally high number of synonymous substitutions accounted for the observed divergence and indicated that such genetic changes may not be completely silent.