Mounting evidence indicates that eradication of HIV infection with highly active antiretroviral therapy (HAART) alone is not possible and remission strategies are needed. Preliminary experience with cytoreductive chemotherapy suggests that it may directly, reduce long-lived pools of infected macrophages and latently-infected lymphocytes in patients with HIV. Cytoreductive therapy such as cyclophosphamide may further enhance the elimination of remaining latently-infected cells inducing a milieu of immune proliferation. In this setting, HAART and GM-CSF are therapies that may inhibit HIV replication and prevent spread of infection to uninfected neighboring cells. This grant represents a plan to study a small cohort of individuals (n=12) with prior prolonged suppression of viremia with HAART that will receive cytoreductive chemotherapy supported by recombinant human GM-CSF and intensified HAART, and that will subsequently stop all therapy and be closely monitored for virologic relapse.
Its specific aims are: 1) To evaluate the potential of cytoreductive chemotherapy supported by GM-CSF in addition to HAART as a strategy for inducing virologic remission of HIV infection; 2) To evaluate the effect of cytoreductive chemotherapy supported by GM-CSF in addition to HAART on reservoirs of HIV and immunologic parameters in HIV infected patients; and 3) To explore immunologic and virologic correlates of virologic relapse in infection in this cohort prospectively discontinuing therapy. This pilot protocol will involve intensive immunologic, virologic and clinical evaluation at all stages of the study, to be accomplished through existing collaborations of established investigators with experience in the conduct of clinical trials, virology and immunology. Accomplishing the aims of this proposal will expand current understanding of the role of cytoreductive therapy in HIV disease and will inform further study of alternative strategies for controlling HIV infection including additional remission strategies under development at UNC-Chapel Hill. However the paramount goal of this career award is to furnish the PI with supervised laboratory experiences and didactic training in addition to a closely supervised clinical research experience, leading to R01 submission and establishment of the PI as an independent investigator
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