Immunologic Approaches To The Therapy Of HIV 1 Infection

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HIV pathogenesis can be summarized as a state of immunodeficiency, reflected by a decline in CD4+ T cell numbers, occurring in a setting of immunosuppression, reflected by levels of HIV in the blood. The peripheral blood CD4+ T cell count reflects the current level of immune competence while the plasma level of HIV RNA reflects the rate at which the CD4 T cell count can be expected to decline. In general, patients do not become ill until the CD4 count drops below a critical threshold. The level of this threshold is dependent upon the amounts of virus in the blood. The higher the plasma levels of HIV, the faster the CD4+ T cel count will decline and the higher the CD4 count at which opportunistic illnesses will develop. Current combination antiretroviral treatment regimens are able to reduce levels of virus and allow for a degree of recovery of the immune system. Unfortunately they are also associated with a significant degree of side effects that become more pronounced over time. The purpose of this project is to develop novel approaches to therapy that target the immune system rather than the virus. A major focus of this project is to examine the role of the T cell derived growth and survival factor interleukin-2 (IL-2) as a treatment strategy based upon expanding the size of the CD4 T cell pool. Over the past year, two phase II trials have been completed and a phase III study has been initiated that examine this approach. In the first multicenter, randomized study, we demonstrated that the intermittent administration of IL-2 was associated with approximately a doubling of the CD4+ T cell count and that recipients of IL-2 had slightly lower levels of HIV in the blood. In the second study, the optimal duration of IL-2 and the optimal interval between cycles were examined in the setting of a randomized, controlled trial. Based upon the data from this later study we concluded that 5 days of IL-2 was the optimal duration for a cycle and that the optimal interval between cycles was no more often than every 8 weeks. These data completed the phase II database required to move to phase III trials and amultinational, phase III study entitled, "Evaluation of Subcutaneous Proleukin in a Randomized, International Trial (ESPRIT)" was initiated.