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Journal of Virology, November 2007, p. 12179-12188, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01277-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Evolution of Human Immunodeficiency Virus Type 1 Cytotoxic T-Lymphocyte Epitopes: Fitness-Balanced Escape

Yi Liu,¹ John McNevin,⁴ Hong Zhao,¹ Denis M. Tebit,⁵ Ryan M. Troyer,⁵ Matthew McSweyn,⁴ Ananta K. Ghosh,^1, Daniel Shriner,¹ Eric J. Arts,⁵ M. Juliana McElrath,^2,3,4 and James I. Mullins^1,2,3*

Departments of Microbiology,¹ Medicine,² Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98195,³ Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,⁴ Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106⁵

Received 12 June 2007/ Accepted 20 August 2007

CD8⁺ cytotoxic T lymphocytes (CTL) are strong mediators of human immunodeficiency virus type 1 (HIV-1) control, yet HIV-1 frequently mutates to escape CTL recognition. In an analysis of sequences in the Los Alamos HIV-1 database, we show that emerging CTL escape mutations were more often present at lower frequencies than the amino acid(s) that they replaced. Furthermore, epitopes that underwent escape contained amino acid sites of high variability, whereas epitopes persisting at high frequencies lacked highly variable sites. We therefore infer that escape mutations are likely to be associated with weak functional constraints on the viral protein. This was supported by an extensive analysis of one subject for whom all escape mutations within defined CTL epitopes were studied and by an analysis of all reported escape mutations of defined CTL epitopes in the HIV Immunology Database. In one of these defined epitopes, escape mutations involving the substitution of amino acids with lower database frequencies occurred, and the epitope soon reverted back to the sensitive form. We further show that this escape mutation substantially diminished viral fitness in in vitro competition assays. Coincident with the reversion in vivo, we observed the fixation of a mutation 3 amino acids C terminal to the epitope, coincident with the ablation of the corresponding CTL response. The C-terminal mutation did not restore replication fitness reduced by the escape mutation in the epitope and by itself had little effect on replication fitness. Therefore, this C-terminal mutation presumably impaired the processing and presentation of the epitope. Finally, for one persistent epitope, CTL cross-reactivity to a mutant form may have suppressed the mutant to undetected levels, whereas for two other persistent epitopes, each of two mutants showed poor cross-reactivity and appeared in the subject at later time points. Thus, a viral dynamic exists between the advantage of immune escape, peptide cross-reactivity, and the disadvantage of lost replication fitness, with the balance playing an important role in determining whether a CTL epitope will persist or decline during infection.

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* Corresponding author. Mailing address: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070. Phone: (206) 732-6163. Fax: (206) 732-6167. E-mail: jmullins{at}u.washington.edu

Published ahead of print on 29 August 2007.

Present address: Biotechnology Centre, Kharagpur-721302, Midnapore, West Bengal, India.

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Journal of Virology, November 2007, p. 12179-12188, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01277-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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