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Journal of Virology, March 2005, p. 3653-3663, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3653-3663.2005

Immunologic Pressure within Class I-Restricted Cognate Human Immunodeficiency Virus Epitopes during Highly Active Antiretroviral Therapy

Joseph P. Casazza,¹ Michael R. Betts,¹ Brenna J. Hill,² Jason M. Brenchley,² David A. Price,² Daniel C. Douek,² and Richard A. Koup^1*

Immunology Laboratory,¹ Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland²

Received 24 June 2004/ Accepted 22 October 2004

Cytotoxic T lymphocytes (CTL) and highly active antiretroviral therapy (HAART) are known to exert strong evolutionary pressures on the virus population during human immunodeficiency virus (HIV) infection. However, it is not known whether CTL responses continue to substantially affect viral evolution during treatment. To study the effect of immunologic pressure on viral sequences during HAART, we identified 10 targeted HIV-specific CD8⁺-T-cell epitopes in five treatment-naïve patients, sequenced each epitope in plasma-derived viruses, and then identified evidence of immunologic pressure at these epitopes by comparing the frequency of viral variants in plasma to the frequency of the CD8⁺-T-cell response for each variant identified. For one of the five patients, evidence of viral evolution was found during therapy. The sequence of the CTL-targeted epitope changed from an apparent escape variant prior to the initiation of therapy, to the sequence that is best recognized by the CTL response after the initiation of therapy, and then finally to a new escape variant during continued therapy. These data show that CTL-mediated pressure can continue to affect viral evolution after the initiation of HAART, even when treatment drives the viral load below detectable levels, and suggest that antiretroviral therapy may preferentially inhibit those virus variants that escape the CTL response.

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* Corresponding author. Mailing address: Building 40, Room 3502, 40 Convent Dr., National Institutes of Health, Bethesda, MD 20892. Phone: (301) 594-8585. Fax: (301) 480-2779. E-mail: rkoup{at}mail.nih.gov.

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Journal of Virology, March 2005, p. 3653-3663, Vol. 79, No. 6
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.6.3653-3663.2005

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