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

Background: Treatments combining T-cell activating agents and potent antire troviral drugs have been proposed as a possible means of reducing the reser voir 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 particu larly potent course of highly active antiretroviral therapy (HAART) were tr eated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Pl asma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other publis hed studies on the use of IL-2 alone were assessed using our mathematical f ramework. Results: We show that outcome of treatment is determined by the relative ra tes of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processe s dominates is critically dependent on both the potency of HAART and also t he degree of T-cell activation induced. We demonstrate that high-level T-ce ll stimulation is likely to produce negative outcomes, both by failing to r educe 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. (C) 2000 Lippinco tt Williams & Wilkins.