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Journal of Virology, December 2003, p. 12572-12578, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12572-12578.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope

Fred W. Peyerl,1 Dan H. Barouch,1 Wendy W. Yeh,1 Heidi S. Bazick,1 Jennifer Kunstman,2 Kevin J. Kunstman,2 Steven M. Wolinsky,2 and Norman L. Letvin1*

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,1 Department of Medicine, Medical School, Northwestern University, Chicago, Illinois 606112

Received 14 July 2003/ Accepted 29 August 2003

Virus-specific cytotoxic T lymphocytes (CTL) exert intense selection pressure on replicating simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) in infected individuals. The immunodominant Mamu-A*01-restricted Gag p11C, C-M epitope is highly conserved among all sequenced isolates of SIV and therefore likely is structurally constrained. The strategies used by virus isolates to mutate away from an immunodominant epitope-specific CTL response are not well defined. Here we demonstrate that the emergence of a position 2 p11C, C-M epitope substitution (T47I) in a simian-human immunodeficiency virus (SHIV) strain 89.6P-infected Mamu-A*01+ monkey is temporally correlated with the emergence of a flanking isoleucine-to-valine substitution at position 71 (I71V) of the capsid protein. An analysis of the SIV and HIV-2 sequences from the Los Alamos HIV Sequence Database revealed a significant association between any position 2 p11C, C-M epitope mutation and the I71V mutation. The T47I mutation alone is associated with significant decreases in viral protein expression, infectivity, and replication, and these deficiencies are restored to wild-type levels with the introduction of the flanking I71V mutation. Together, these data suggest that a compensatory mutation is selected for in SHIV strain 89.6P to facilitate the escape of that virus from CTL recognition of the dominant p11C, C-M epitope.

* Corresponding author. Mailing address: Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Viral Pathogenesis, Research East Room 113, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-2766. Fax: (617) 667-8210. E-mail: nletvin{at}bidmc.harvard.edu.

Journal of Virology, December 2003, p. 12572-12578, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12572-12578.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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