Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost

Caroline S. Fernandez, Ivan Stratov, Robert De Rose, Katrina Walsh, C. Jane Dale, Miranda Z. Smith, Michael B. Agy, Shiu Lok Hu, Kendall Krebs, David I. Watkins, David H. O'Connor, Miles P. Davenport, Stephen J. Kent

Research output: Contribution to journalArticle

146 Scopus citations

Abstract

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 SIHVSF162P3. 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.

Original languageEnglish (US)
Pages (from-to)5721-5731
Number of pages11
JournalJournal of virology
Volume79
Issue number9
DOIs
StatePublished - May 2005

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Fernandez, C. S., Stratov, I., De Rose, R., Walsh, K., Dale, C. J., Smith, M. Z., Agy, M. B., Hu, S. L., Krebs, K., Watkins, D. I., O'Connor, D. H., Davenport, M. P., & Kent, S. J. (2005). Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost. Journal of virology, 79(9), 5721-5731. https://doi.org/10.1128/JVI.79.9.5721-5731.2005