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Journal of Virology, May 2005, p. 5721-5731, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5721-5731.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Rapid Viral Escape at an Immunodominant Simian-Human Immunodeficiency Virus Cytotoxic T-Lymphocyte Epitope Exacts a Dramatic Fitness Cost

Caroline S. Fernandez,^1, Ivan Stratov,^1, Robert De Rose,¹ Katrina Walsh,¹ C. Jane Dale,¹ Miranda Z. Smith,¹ Michael B. Agy,² Shiu-lok Hu,² Kendall Krebs,³ David I. Watkins,³ David H. O'Connor,³ Miles P. Davenport,⁴ and Stephen J. Kent^*

Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia,¹ National Primate Research Centre, University of Washington, Seattle, WA 98105,² National Primate Research Centre, University of Wisconsin, Madison WI 53715,³ Department of Haematology, Prince of Wales Hospital, and Centre for Vascular Research, University of New South Wales, Kensington, NSW 2052, Australia⁴

Received 8 August 2004/ Accepted 6 December 2004

Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched individuals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIV_SF162P3. Another challenge virus, SHIV_mn229, previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.

Contributed equally to the work.

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