The Journal of Experimental Medicine
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Published 29 October 2001. doi:10.1084/jem.194.9.1277
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© Rockefeller University Press, 0022-1007/2001/11/1277/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 9, November 5, 2001 1277-1288

Original Article

 Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy

Hiroshi Mohri1, Alan S. Perelson2, Keith Tung1, Ruy M. Ribeiro2, Bharat Ramratnam1, Martin Markowitz1, Rhonda Kost1, Hurley1, Leor Weinberger2, Denise Cesar3,4, Marc K. Hellerstein3,4 and David D. Ho1

1 Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016
2 Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545
3 Department of Nutritional Sciences, University of California at Berkeley, Berkeley, CA 94720
4 Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, CA 94110

Address correspondence to David D. Ho, Aaron Diamond AIDS Research Center, 455 First Ave., New York, NY 10016. Phone: 212-448-5100; Fax: 212-725-1126; E-mail: dho{at}adarc.org

The mechanism of CD4+ T cell depletion in human immunodeficiency virus (HIV)-1 infection remains controversial. Using deuterated glucose to label the DNA of proliferating cells in vivo, we studied T cell dynamics in four normal subjects and seven HIV-1–infected patients naive to antiretroviral drugs. The results were analyzed using a newly developed mathematical model to determine fractional rates of lymphocyte proliferation and death. In CD4+ T cells, mean proliferation and death rates were elevated by 6.3- and 2.9-fold, respectively, in infected patients compared with normal controls. In CD8+ T cells, the mean proliferation rate was 7.7-fold higher in HIV-1 infection, but the mean death rate was not significantly increased. Five of the infected patients underwent subsequent deuterated glucose labeling studies after initiating antiretroviral therapy. The lymphocyte proliferation and death rates in both CD4+ and CD8+ cell populations were substantially reduced by 5–11 weeks and nearly normal by one year. Taken together, these new findings strongly indicate that CD4+ lymphocyte depletion seen in AIDS is primarily a consequence of increased cellular destruction, not decreased cellular production.

Key Words: deuterated glucose • longitudinal study • mathematical model • apoptosis • mechanisms of CD4+ T cell depletion


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