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

被引:31
作者
Günthard, HF
Leigh-Brown, AJ
D'Aquila, RT
Johnson, VA
Kuritzkes, DR
Richman, DD
Wong, JK
机构
[1] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[3] San Diego Vet Affairs Med Ctr, La Jolla, CA 92093 USA
[4] Univ Edinburgh, Ctr HIV Res, Edinburgh EH9 3JN, Midlothian, Scotland
[5] Massachusetts Gen Hosp, Charlestown, MA 02129 USA
[6] Harvard Univ, Sch Med, Charlestown, MA 02129 USA
[7] Univ Alabama, Sch Med, Dept Med, Birmingham, AL 35294 USA
[8] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA
[9] Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA
关键词
D O I
10.1006/viro.1999.9774
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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. (C) 1999 Academic Press.
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页码:154 / 165
页数:12
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