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Journal of Virology, August 2005, p. 10627-10637, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10627-10637.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Effect of a Protease Inhibitor-Induced Genetic Bottleneck on Human Immunodeficiency Virus Type 1 env Gene Populations

Kathryn M. Kitrinos,^1,2, Julie A. E. Nelson,^1, Wolfgang Resch,^1,3, and Ronald Swanstrom^1,3*

UNC Center for AIDS Research,¹ Curriculum of Genetics and Molecular Biology,² Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, 22-062 Lineberger Cancer Center, CB 7295, Chapel Hill, North Carolina 27599-7295³

Received 3 July 2004/ Accepted 12 November 2004

The initiation of drug therapy or the addition of a new drug to preexisting therapy can have a significant impact on human immunodeficiency virus type 1 (HIV-1) populations within a person. Drug therapy directed at reverse transcriptase and protease can result in dramatic decreases in virus load, causing a contraction in the virus population that represents a potential genetic bottleneck as a subset of virus with genomes carrying resistance mutations repopulate the host. While this bottleneck exerts an effect directly on the region that is being targeted by the drugs, it also affects other regions of the viral genome. We have applied heteroduplex tracking assays (HTA) specific to variable regions 1 and 2 (V1/V2) and variable region 3 (V3) of the HIV-1 env gene to analyze the effect of a genetic bottleneck created by the selection of resistance to ritonavir, a protease inhibitor. Subjects were classified into groups on the basis of the extent of the initial drop in virus load and the duration of virus load reduction. Subjects with a strong initial drop in virus load exhibited a loss of heterogeneity in the env region at virus load rebound; in contrast, subjects with a weak initial drop in virus load exhibited little to no loss of heterogeneity at virus load rebound in either region of env examined. The duration of virus load reduction also affected env populations. Subjects that had prolonged reductions exhibited slower population diversification and the appearance of new V1/V2 species after rebound. The longer reduction of virus load in these subjects may have allowed for improved immune system function, which in turn could have selected for new escape mutants. Subjects with rapid rebound quickly reequilibrated the entry env variants back into the resistant population. When the pro gene developed further resistance mutations subsequent to virus load rebound, no changes were observed in V1/V2 or V3 populations, suggesting that the high virus loads allowed the env populations to reequilibrate rapidly. The rapid equilibration of env variants during pro gene sequence transitions at high virus load suggests that recombination is active in defining the HIV-1 sequence population. Conversely, part of the success of suppressive antiviral therapy may be to limit the potential for evolution through recombination, which requires dually infected cells.

Present address: International Clinical Virology, GlaxoSmithKline, P.O. Box 13398, 5 Moore Drive, RTP, NC 27709-3398.

Present address: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, P.O. Box 670524, Cincinnati, OH 45267-0524.

Present address: Laboratory of Viral Diseases, Building 4, 4 Center Drive, MSC0445, NIAID, National Institutes of Health, Bethesda, MD 20892-0445.

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