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Journal of Virology, July 2000, p. 6262-6268, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Evolution of Lamivudine Resistance in Human Immunodeficiency Virus Type 1-Infected Individuals: the Relative Roles of Drift and Selection

Simon D. W. Frost,1,* Monique Nijhuis,2 Rob Schuurman,2 Charles A. B. Boucher,2 and Andrew J. Leigh Brown1

Centre for HIV Research, Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, Scotland,1 and Eijkman-Winkler Institute, Department of Virology, University Hospital Utrecht, Utrecht, The Netherlands2

Received 20 December 1999/Accepted 19 April 2000

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V results in a drop in viral load only in individuals with high CD4+ counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0.2:1, with a range from 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.

* Corresponding author. Mailing address: Centre for HIV Research, Institute of Cell, Animal and Population Biology, Waddington Building, King's Buildings, West Mains Rd., Edinburgh EH9 3JN, Scotland. Phone: 44 (0)131 650 8678. Fax: 44 (0)131 650 8678. E-mail: simon.frost{at}ed.ac.uk.

Journal of Virology, July 2000, p. 6262-6268, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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