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J. Biol. Chem., Vol. 279, Issue 25, 26726-26734, June 18, 2004

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Purifying Selection Masks the Mutational Flexibility of HIV-1 Reverse Transcriptase^*

Robert A. Smith, Donovan J. Anderson, and Bradley D. Preston

From the Department of Pathology, University of Washington, Seattle, Washington 98195

DNA and RNA polymerases share a core architecture composed 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 10 of the 11 amino acid positions examined. These included residues that 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.

Received for publication, December 22, 2003 , and in revised form, March 1, 2004.

^* This work was supported by National Institutes of Health Grants RO1 AI34834 (to B. P.) and F32 AI10139 (to R. S.) and by the University of Utah Undergraduate Research Opportunities Program (to D. A.).

To whom correspondence should be addressed: Dept. of Pathology, K-072 Health Sciences Bldg., Box 357705, 1959 N.E. Pacific St., Seattle, WA 98195-7705. Tel.: 206-616-5062; Fax: 206-543-3967; E-mail: bradp{at}u.washington.edu.

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