Sequence and drug susceptibility of subtype C reverse transcriptase from human immunodeficiency virus type 1 seroconverters in Zimbabwe

Abstract

Naturally occurring human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) variability has implications for the success of antiretroviral therapy. We determined the sequence of the polymerase-coding region of RT from virus isolates from 12 Zimbabwean individuals recently infected with HIV-1. The 12 RT sequences differed from the consensus B RT sequence at 10.5% of nucleotides and 5.8% of amino acids. Susceptibility testing of five isolates to zidovudine, didanosine, lamivudine, and nevirapine demonstrated susceptibilities similar to those of wild-type subtype B isolates. Phylogenetic analysis of 40 HIV-1 RT sequences, including the 12 Zimbabwean subtype C sequences, 11 subtype B sequences, and the 17 remaining published non-subtype B sequences showed sufficient intrasubtype RT sequence variation to differentiate subtype A, B, C, and D isolates. Five recently reported subtype C RT sequences from India grouped with the Zimbabwean subtype C sequences but had significantly less intraisolate sequence variation. Both intra- and intersubtype RT comparisons were notable for extraordinarily high ratios of synonymous to nonsynonymous differences. Although substitutions in the HIV-1 RT gene are limited by functional constraints, variation between RT sequences demonstrates phylogenetic relationships that parallel env and gag gene variation.HIV-1 genetic variation is one of the major obstacles to the development of a safe and effective vaccine. Subtype C is one of the most prevalent HIV-1 subtypes and is especially common in Africa and India. The authors report their findings from research conducted to determine the reverse transcriptase (RT) sequence of the polymerase-coding region of 12 subtype C isolates from recently HIV-1-infected individuals in Zimbabwe. The authors also assessed the susceptibility of 5 of the isolates to nucleoside analog and non-nucleoside RT inhibitors. The 12 RT sequences differed from the consensus B RT sequence at 10.5% of nucleotides and 5.8% of amino acids. Susceptibility testing of the five isolates to zidovudine, didanosine, lamivudine, and nevirapine identified susceptibilities similar to those of wild-type subtype B isolates. Phylogenetic analysis of 40 HIV-1 RT sequences, including the 12 Zimbabwean subtype C sequences, 11 subtype B sequences, and 17 published non-subtype B sequences found sufficient intrasubtype RT sequence variation to differentiate subtype A, B, C, and D isolates. 5 recently reported subtype C RT sequences from India grouped with the Zimbabwean subtype C sequences, but had significantly less intraisolate sequence variation. There were extremely high ratios of synonymous to nonsynonymous differences in both intra- and intersubtype RT comparisons.