Higher selection pressure from antiretroviral drugs in vivo results in increased evolutionary distance in HIV-1 pol

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 R T 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 substi tutions and for synonymous and nonsynonymous substitutions separately. At w eek 8 when HIV RNA reduction (selection pressure) was high, significantly m ore divergence in pol in both synonymous and nonsynonymous substitutions wa s found in patients with substantial RNA reduction (strong responders). Sep arate analyses of PR and RT revealed significantly greater ED in the RT (un der selection pressure) of strong compared with nonresponders, whereas dive rgence between PR genes (not under selection pressure) did not differ in th ose two groups. Such differential evolution indicates that PR and RT were g enetically unlinked and suggests recombination. The rapid increase of ED ov er the first 8 weeks was followed by only a minimal further rise by week 48 , suggesting that selection of preexisting quasispecies accounted for the e arly changes. A disproportionally high number of synonymous substitutions a ccounted for the observed divergence and indicated that such genetic change s may not be completely silent. (C) 1999 Academic Press.