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Journal of Virology, June 2003, p. 6743-6752, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6743-6752.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Dual Pressure from Antiretroviral Therapy and Cell-Mediated Immune Response on the Human Immunodeficiency Virus Type 1 Protease Gene

Annika C. Karlsson,1* Steven G. Deeks,2 Jason D. Barbour,1 Brandon D. Heiken,1 Sophie R. Younger,1 Rebecca Hoh,2 Meghan Lane,2 Matti Sällberg,3 Gabriel M. Ortiz,1 James F. Demarest,4 Teri Liegler,1 Robert M. Grant,1,2 Jeffrey N. Martin,2 and Douglas F. Nixon1,2

Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94141,1 Department of Medicine, University of California, San Francisco, and San Francisco General Hospital, San Francisco, California 94110,2 Division of Clinical Virology, Karolinska Institute, Huddinge University Hospital, 141 86 Stockholm, Sweden,3 Clinical Virology, GlaxoSmithKline, Research Triangle Park, North Carolina 277094

Received 21 January 2003/ Accepted 26 March 2003

Human immunodeficiency virus (HIV)-specific CD8+ T-lymphocyte pressure can lead to the development of viral escape mutants, with consequent loss of immune control. Antiretroviral drugs also exert selection pressures on HIV, leading to the emergence of drug resistance mutations and increased levels of viral replication. We have determined a minimal epitope of HIV protease, amino acids 76 to 84, towards which a CD8+ T-lymphocyte response is directed. This epitope, which is HLA-A2 restricted, includes two amino acids that commonly mutate (V82A and I84V) in the face of protease inhibitor therapy. Among 29 HIV-infected patients who were treated with protease inhibitors and who had developed resistance to these drugs, we show that the wild-type PR82V76-84 epitope is commonly recognized by cytotoxic T lymphocytes (CTL) in HLA-A2-positive patients and that the CTL directed to this epitope are of high avidity. In contrast, the mutant PR82A76-84 epitope is generally not recognized by wild-type-specific CTL, or when recognized it is of low to moderate avidity, suggesting that the protease inhibitor-selected V82A mutation acts both as a CTL and protease inhibitor escape mutant. Paradoxically, the absence of a mutation at position 82 was associated with the presence of a high-avidity CD8+ T-cell response to the wild-type virus sequence. Our results indicate that both HIV type 1-specific CD8+ T cells and antiretroviral drugs provide complex pressures on the same amino acid sequence of the HIV protease gene and, thus, can influence viral sequence evolution.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, University of California, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3826. Fax: (415) 826-8449. E-mail: akarlsson{at}gladstone.ucsf.edu.

Journal of Virology, June 2003, p. 6743-6752, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6743-6752.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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