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Journal of Virology, July 2005, p. 8171-8181, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8171-8181.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection

Tomohiko Koibuchi,1 Todd M. Allen,1 Mathias Lichterfeld,1 Stanley K. Mui,1 Kristin M. O'Sullivan,1 Alicja Trocha,1,2 Spyros A. Kalams,3 R. Paul Johnson,4 and Bruce D. Walker1,2*

Partners AIDS Research Center, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts,1 Howard Hughes Medical Institute, Chevy Chase, Maryland,2 Infectious Diseases Unit, Department of Internal Medicine, and Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee,3 New England Primate Research Center, Southborough, Massachusetts4

Received 22 October 2004/ Accepted 6 March 2005

Studies in acute human immunodeficiency virus type 1 (HIV-1) infection indicate viral evolution under CD8 T-cell immune selection pressure, but the effects of ongoing immune pressure on epitope evolution during chronic infection are not well described. In this study, we performed a detailed longitudinal analysis of viral sequence variation within persistently targeted cytotoxic T-lymphocyte (CTL) epitopes in two HIV-1-infected persons during 6 years of persistent viremia. Responses were quantitated using freshly isolated peripheral blood lymphocytes in direct lytic assays as well as by gamma interferon (IFN-{gamma}) Elispot assays on cryopreserved cells. Seven targeted epitopes were identified in each person. In the majority of cases, the dominant epitope sequence did not change over time, even in the presence of responses of sufficient magnitude that they were detectable using fresh peripheral blood mononuclear cells in direct lytic assays. Only 4 of the 14 autologous epitopes tested represented potential CTL escape variants; however, in most cases strong responses to these epitopes persisted for the 6 years of study. Although persistent IFN-{gamma} responses were detected to all epitopes, direct lytic assays demonstrated declining responses to some epitopes despite the persistence of the targeted sequence in vivo. These data indicate limited viral evolution within persistently targeted CD8 T-cell epitopes during the chronic phase of infection and suggest that these regions of the virus are either refractory to sequence change or that persistently activated CD8 T-cell responses in chronic infection exert little functional selection pressure.

* Corresponding author. Mailing address: Howard Hughes Medical Institute and Partners AIDS Research Center, Massachusetts General Hospital, Bldg. 149, 13th Street, Charlestown, MA 02129. Phone: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker{at}partners.org.

Journal of Virology, July 2005, p. 8171-8181, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8171-8181.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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