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Papers In Press, published online ahead of print March 9, 2004
Department of Pathology, University of Washington, Seattle, WA 98195-7705
Corresponding Author: bradp{at}u.washington.edu
DNA and RNA polymerases share a core architecture comprised of three structurally conserved motifs: A, B and C. Although the amino acid sequences of these motifs are highly conserved between closely related organisms, variation across broader evolutionary distances suggests that only a few residues in each motif are indispensable for polymerase function. To test this, we constructed libraries of human immunodeficiency virus type-1 (HIV-1) containing random single amino acid replacements in motif B of reverse transcriptase (RT), and we used selection in culture to assess RT function. Despite the nearly absolute constancy of motif B in vivo, virus replicating in culture tolerated a range of conservative and nonconservative substitutions at ten of the eleven amino acid positions examined. These included residues which are invariant across all retroviral subfamilies and highly conversed in diverse retroelements. Several mutants retained wild type infectivity, and serial passage experiments revealed replacements that were neutral or even beneficial to viral fitness. In addition, a number of the selected variants exhibited altered susceptibility to the nucleoside analog inhibitors AZT and 3TC. Taken together, these data indicate that HIV-1 tolerates a range of substitutions at conserved RT residues and that selection against slightly deleterious mutations (purifying selection) in vivo masks a large repertoire of viable phenotypic variants. This mutational flexibility likely contributes to HIV-1 evolution in response to changing selection pressures in infected individuals.
J. Biol. Chem, 10.1074/jbc.M314038200
Submitted on December 22, 2003
Revised on March 1, 2004
Accepted on March 9, 2004
Purifying selection masks the mutational flexibility of HIV-1 reverse transcriptase
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