Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy.
OBJECTIVE: Combination antiretroviral therapy in a subset of HIV-infected patients, here called CD4-low responders (CD4-LR), fails to produce a rapid rise in CD4 cell counts despite effective control of plasma viral load (< 50 copies/ml). The mechanism responsible for this failure was investigated. DESIGN AND METHODS: CD4-LR patients (n = 13) included in the study had been receiving stable antiretroviral therapy for > 9 months, resulting in undetectable viral load, but nontheless showed a CD4 cell count of < 200 x 106 cells/l. Samples from these patients were analysed for intracellular expression of the anti-apoptotic molecule Bcl-2 and the in vitro apoptosis of their CD4 lymphocytes. Since interleukin-2 (IL-2) induces Bcl-2 and participates in the control of lymphocyte apoptosis, we also investigated the IL-2/ IL-2 receptor ( IL-2R) system in these CD4-LR patients. All these investigations were performed before and after the CD4-LR patients received IL-2 therapy. RESULTS: CD4 T lymphocytes from these patients underexpressed the anti-apoptotic molecule Bcl-2 and were more susceptible to spontaneous apoptosis. Peripheral CD4 T lymphocytes from the CD4-LR patients showed a regulatory dysfunction in the IL-2R system that resulted in a lack of reactivity to IL-2. Overall, the results obtained with CD4-LR patients differed radically from those in patients undergoing successful antiretroviral therapy. Finally, an increase in Bcl-2 expression and IL-2 reactivity was observed in the CD4 T lymphocytes of CD4-LR patients receiving IL-2 immunotherapy. This correlated with a reduction in their apoptosis. CONCLUSION: Our study characterizes the defective maintenance of peripheral CD4 T lymphocytes in CD4-LR patients, probably resulting from Bcl-2 underexpression and dysregulation of the IL-2R system.[1]References
- Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy. David, D., Keller, H., Naït-Ighil, L., Treilhou, M.P., Joussemet, M., Dupont, B., Gachot, B., Maral, J., Thèze, J. AIDS (2002) [Pubmed]
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