Divergent evolution in reverse transcriptase (RT) of HIV-1 group O and M lineages: impact on structure, fitness, and sensitivity to nonnucleoside RT inhibitors.

Journal of Virology
Denis M TebitEric J Arts

Abstract

Natural evolution in primate lentiviral reverse transcriptase (RT) appears to have been constrained by the necessity to maintain function within an asymmetric protein composed of two identical primary amino acid sequences (66 kDa), of which one is cleaved (51 kDa). In this study, a detailed phylogenetic analysis now segregates groups O and M into clusters based on a cysteine or tyrosine residue located at position 181 of RT and linked to other signature residues. Divergent evolution of two group O (C181 or Y181) and the main (Y181 only) HIV-1 lineages did not appreciably impact RT activity or function. Group O RT structural models, based on group M subtype B RT crystal structures, revealed that most evolutionarily linked amino acids appear on a surface-exposed region of one subunit while in a noncatalytic RT pocket of the other subunit. This pocket binds nonnucleoside RT inhibitors (NNRTI); therefore, NNRTI sensitivity was used to probe enzyme differences in these group O and M lineages. In contrast to observations showing acquired drug resistance associated with fitness loss, the C181Y mutation in the C181 group O lineage resulted in a loss of intrinsic NNRTI resistance and was accompanied by fitness loss. Other mutations link...Continue Reading

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Citations

Apr 5, 2012·Cold Spring Harbor Perspectives in Medicine·Eric J Arts, Daria J Hazuda
Mar 27, 2013·Antimicrobial Agents and Chemotherapy·Michael A LobritzEric J Arts
Feb 15, 2012·Antimicrobial Agents and Chemotherapy·André F A SantosEric J Arts
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Feb 11, 2016·AIDS Research and Human Retroviruses·Denis M TebitEric J Arts

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