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Conference
"Immune-Based Intervention in HIV Infection" Dr. Giuseppe Pantaleo (biography) English - 2002-04-15 - 37 minutes
Summary : A major feature of primary HIV-1 infection is the massive immune activation. The immune activation may be deleterious for several reasons. Although HIV-1 may replicate in both quiescent and activated CD4+ T cells, proliferating and activated CD4+ T cells support massive HIV-1 replication and production. High levels of virus replication and massive stimulation of the immune system may lead to clonal exhaustion of HIV-specific CD8+ T cells and rapid elimination of virus-specific CD4+ T helper cells.
For these reasons, few studies in the past have tested in HIV-1 infection the therapeutic effects of therapeutic agents such as Cyclosporin A (CsA) that selectively suppresses T cell activation. CsA, a cyclic undecapeptide, is an immunosuppressive agent which has been hypothesized to suppress HIV-1 replication indirectly by limiting T cell activation, and directly by interference with HIV-1 gag polyprotein processing resulting in production of non-infectious particles. CsA suppresses T-cell activation by directly blocking activation of the genes for interleukin (IL)-2, IL-4 and the IL-2 receptor in T cells, thus inhibiting IL-2 dependent T cell proliferation and differentiation. The results from the above clinical studies were quite disappointing since there was no evidence for a beneficial effect. In this regard, it is important to underscore that in these studies CsA was used as monotherapy in patients with chronic infection and at advanced stages of disease. However, administration of CsA in monkeys acutely inoculated with SIV showed a beneficial effect on the kinetics of CD4 depletion. The results obtained in the SIV model of primary infection supported the rationale of careful exploration of the strategy of interference with the heightened state of immune activation in combination with HAART in primary HIV-1 infection.
Recently, another immunosuppressive drug, e.g. mycophenolate mophetil, has been used in pilot studies in HIV-1 infection. In principle, mycophenolate mophetil may inhibit HIV-1 replication by a direct effect, e.g. depletion of the guanosine nucleotide pool (critical substrate for the completion of reverse transcription), and by an indirect effect, e.g. suppression of T cell activation. Mycophenolate mophetil is an inhibitor of inosine monophosphate dehydrogenase, an enzyme critical for effective protein synthesis. The inhibitory activity of mycophenolate mophetil is highly selective on B and T lymphocytes. Evidence will be presented that the rapid shutdown of the immune activation associated to HIV-1 infection may be beneficial for both immunologic and virologic measures.
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