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T Cell Division in HIV-1 Infection Is Mainly Caused By Immune Activation: A Longitudinal Analysis in Patients before and during HAART M. D. HAZENBERG1, J. W. T. COHEN STUART3,4, S. A. OTTO1, J. C. C. BORLEFFS4, C. A. B. BOUCHER3, R. J. DE BOER5, F. MIEDEMA1,2, and D. HAMANN*1.
1Clin. Viro-Immunology, CLB; 2Human Retrovirology, AMC, Amsterdam; 3Eijkman-Winkler Inst.; and 4Utrecht Univ. and Univ. Hosp., The Netherlands In HIV-1 infection, highly increased T cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4+ and CD8+ lymphocyte subpopulations before and during HAART.
Results: In untreated HIV-1 infection, both the percentage and number of Ki-67+ CD4+ and CD8+ lymphocytes were significantly increased, as compared to values obtained from healthy individuals. A more then 10-fold increase in the percentage of dividing naive CD4+ T cells in the blood was found when the number of these cells was below 100 per mm3. HAART induced an immediate decline in Ki-67 expression despite often very low CD4+ T cell numbers, arguing against increased proliferation being a homeostatic response. In the CD8+ T cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27+ and CD27- CD45RO+ memory CD8 + T cell pool, corresponding to the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8+ T cell subsets.
Conclusion: Peripheral T-cell proliferation is a consequence of generalized immune activation, rather then a response to, or the cause of, lymphocyte depletion.
Key Words: CD4 depletion, pathogenisis, T cell division
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