Abstract
The dynamic basis for T-cell depletion in late-stage HIV-1 disease remains controversial. Using a new, non-radioactive, endogenous labeling technique1, we report direct measurements of circulating T-cell kinetics in normal and in HIV-1-infected humans. In healthy, HIV-1-seronegative subjects, CD4+ and CD8+ T cells had half-lives of 87 days and 77 days, respectively, with absolute production rates of 10 CD4+ T cells/μl per day and 6 CD8+ T cells/μl per day. In untreated HIV-1-infected subjects (with a mean CD4 level of 342 cells/μl), the half-life of each subpopulation was less than 1/3 as long as those of healthy, HIV-1-seronegative subjects but was not compensated by an increased absolute production rate of CD4+ T cells. After viral replication was suppressed by highly active antiretroviral therapy for 12 weeks, the production rates of circulating CD4+ and CD8+ T cells were considerably elevated; the kinetic basis of increased CD4 levels was greater production, not a longer half-life, of circulating cells. These direct measurements indicate that CD4+ T-cell lymphopenia is due to both a shortened survival time and a failure to increase the production of circulating CD4+ T cells. Our results focus attention on T-cell production systems in the pathogenesis of HIV-1 disease and the response to antiretroviral therapy.
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Acknowledgements
We thank the individuals who participated in this study, as well as Project Inform and other members of the Bay Area AIDS community for support, H.C. Lane for technical support, and R.M. Grant for his reading of the manuscript. This work was supported by grants from the NIH, the UCSF Center for AIDS Research and SpectruMedix (to M.K.H.) and from the NIH, the UCSF Center for AIDS Research, the UCSF/Macy's Center for Creative Therapies and the Gladstone Institute (to J.M.M.). J.M.M. is an Elizabeth Glaser Scientist supported by the Elizabeth Glaser Pediatric AIDS Foundation. An NIH Grant from the Division of Research Resources supported the General Clinical Research Center. D.M. received funds from a Medical Research Council (UK) Traveling Fellowship.
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Hellerstein, M., Hanley, M., Cesar, D. et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 5, 83–89 (1999). https://doi.org/10.1038/4772
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DOI: https://doi.org/10.1038/4772
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