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Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs

Fraser, Christophe; Ferguson, Neil M.; Ghani, Azra C.; Prins, Jan M.a; Lange, Joep M. A.a; Goudsmit, Jaapb; Anderson, Roy M.; de Wolf, Frankb


Background: Treatments combining T-cell activating agents and potent antiretroviral drugs have been proposed as a possible means of reducing the reservoir of long-lived HIV-1 infected quiescent CD4 T-cells.

Objective: To analyse the effect of such therapies on HIV-1 dynamics and T-cell homeostasis.

Design and methods: A mathematical framework describing HIV-1 dynamics and T-cell homeostasis was developed. Three patients who were kept on a particularly potent course of highly active antiretroviral therapy (HAART) were treated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Plasma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other published studies on the use of IL-2 alone were assessed using our mathematical framework.

Results: We show that outcome of treatment is determined by the relative rates of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processes dominates is critically dependent on both the potency of HAART and also the degree of T-cell activation induced. We demonstrate that high-level T-cell stimulation is likely to produce negative outcomes, both by failing to reduce viral reservoirs and by depleting the CD4 T-cell pool and disrupting CD4/CD8 T-cell homeostasis. In contrast, repeated low-level stimulation may both aid CD4 T-cell pool expansion and achieve a substantial reduction in the long-lived HIV-1 reservoir.

Conclusions: Our analysis suggests that although treatment that activates T-cells can reduce the long-lived HIV-1 reservoir, caution should be used as high-level stimulation may result in a negative outcome.

From the Wellcome Trust Centre for the Epidemiology of Infectious Disease, University of Oxford, UK, and the aDepartment of Internal Medicine and the National AIDS therapy evaluation Centre and bthe Department of Human Retrovirology, University of Amsterdam, Academic Medical Centre, The Netherlands.

Sponsorship: The OKT3/IL-2 study was supported financially by a Dutch private fund that wishes to remain anonymous. C. F., A. G. and R. A. were funded by the Wellcome Trust and N. F. was funded by the Royal Society.

Requests for reprints to: C. Fraser, The Wellcome Trust Centre for the Epidemiology of Infectious Disease, University of Oxford, South Parks Road, Oxford OX1 3FY, UK.

Received: 9 September 1999;

revised: 8 December 1999; accepted: 19 January 2000.

© 2000 Lippincott Williams & Wilkins, Inc.