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Journal of Virology, September 2004, p. 10064-10073, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.10064-10073.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Consequences of Cytotoxic T-Lymphocyte Escape: Common Escape Mutations in Simian Immunodeficiency Virus Are Poorly Recognized in Naïve Hosts

Thomas C. Friedrich,1 Adrian B. McDermott,2 Matthew R. Reynolds,2 Shari Piaskowski,1 Sarah Fuenger,1 Ivna P. de Souza,2 Richard Rudersdorf,1 Candice Cullen,1 Levi J. Yant,2 Lara Vojnov,2 Jason Stephany,2 Sarah Martin,1 David H. O'Connor,2 Nancy Wilson,1 and David I. Watkins1,2*

Wisconsin National Primate Research Center,1 Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, Wisconsin2

Received 29 December 2003/ Accepted 7 May 2004

Cytotoxic T lymphocytes (CTL) are associated with control of immunodeficiency virus infection but also select for variants that escape immune recognition. Declining frequencies of epitope-specific CTL frequencies have been correlated with viral escape in individual hosts. However, escape mutations may give rise to new epitopes that could be recognized by CTL expressing appropriate T-cell receptors and thus still be immunogenic when escape variants are passed to individuals expressing the appropriate major histocompatibility complex class I molecules. To determine whether peptide ligands that have been altered through escape can be immunogenic in new hosts, we challenged naïve, immunocompetent macaques with a molecularly cloned simian immunodeficiency virus (SIV) bearing common escape mutations in three immunodominant CTL epitopes. Responses to the altered peptides were barely detectable in fresh samples at any time after infection. Surprisingly, CTL specific for two of three escaped epitopes could be expanded by in vitro stimulation with synthetic peptides. Our results suggest that some escape variant epitopes evolving in infected individuals do not efficiently stimulate new populations of CTL, either in that individual or upon passage to new hosts. Nevertheless, escape variation may not completely abolish an epitope's immunogenicity. Moreover, since the mutant epitope sequences did not revert to wild type during the study period, it is possible that low-frequency CTL exerted enough selective pressure to preserve epitope mutations in viruses replicating in vivo.

* Corresponding author. Mailing address: Wisconsin National Primate Research Center, 1220 Capitol Court, Madison, WI 53715. Phone: (608) 265-3380. Fax: (608) 265-3380. E-mail: watkins{at}primate.wisc.edu.

Journal of Virology, September 2004, p. 10064-10073, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.10064-10073.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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