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Blood, Vol. 95 No. 1 (January 1), 2000: pp. 249-255

T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART)

Mette D. Hazenberg, James W. T. Cohen Stuart, Sigrid A. Otto, Jan C. C. Borleffs, Charles A. B. Boucher, Rob J. de Boer, Frank Miedema, and Dörte Hamann

From the Department of Clinical Viro-Immunology, CLB, and the Laboratory for Experimental and Clinical Immunology and Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Internal Medicine, University Hospital Utrecht; the Department of Virology, Eijkman-Winkler Institute, University Hospital Utrecht; and the Department of Theoretical Biology, Utrecht University, Utrecht, The Netherlands.

In human immunodeficiency virus (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 highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67+ CD4+ and CD8+ lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4+ T cells in the blood was found when the number of these cells were below 100 per µL.. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4+ T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4+ CD27+ memory pool. 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+ CD 45RO+ and CD27- CD45RO+ memory CD8+ T-cell pool, corresponding with 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. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)


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