The Journal of Experimental Medicine
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Published online 12 May 2003 doi:10.1084/jem.20022138
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© Rockefeller University Press, 0022-1007/2003/5/1365 $5.00
The Journal of Experimental Medicine, Volume 197, Number 10, 1365-1375

Determinants of HIV-1 Mutational Escape From Cytotoxic T Lymphocytes

Otto O. Yang1, Phuong Thi Nguyen Sarkis2, Ayub Ali1, Jason D. Harlow2, Christian Brander2, Spyros A. Kalams2 and Bruce D. Walker2

1 Division of Infectious Diseases, 37-121 CHS, UCLA Medical Center, Los Angeles, CA 90095
2 Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital-East, Charlestown, MA 02129

Address correspondence to Otto O. Yang, Division of Infectious Diseases, 37-121 CHS, UCLA Medical Center, 10833 LeConte Ave., Los Angeles, CA 90095. Phone: 310-794-9491; Fax: 310-825-3632; E-mail: oyang{at}mednet.ucla.edu

CD8+ class I–restricted cytotoxic T lymphocytes (CTLs) usually incompletely suppress HIV-1 in vivo, and while analogous partial suppression induces antiretroviral drug-resistance mutations, epitope escape mutations are inconsistently observed. However, escape mutation depends on the net balance of selective pressure and mutational fitness costs, which are poorly understood and difficult to study in vivo. Here we used a controlled in vitro system to evaluate the ability of HIV-1 to escape from CTL clones, finding that virus replicating under selective pressure rapidly can develop phenotypic resistance associated with genotypic changes. Escape varied between clones recognizing the same Gag epitope or different Gag and RT epitopes, indicating the influence of the T cell receptor on pressure and fitness costs. Gag and RT escape mutations were monoclonal intra-epitope substitutions, indicating limitation by fitness constraints in structural proteins. In contrast, escape from Nef-specific CTL was more rapid and consistent, marked by a polyclonal mixture of epitope point mutations and upstream frameshifts. We conclude that incomplete viral suppression by CTL can result in rapid emergence of immune escape, but the likelihood is strongly determined by factors influencing the fitness costs of the particular epitope targeted and the ability of responding CTL to recognize specific epitope variants.

Key Words: cellular immunity • T cell receptor • antigenic variation • T cell receptor specificity


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