HIV Persistence and Cardiopulmonary Disease

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 DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is increased more than 10-times in patients with HIV compared to the general population. Endothelial cell proliferation driven by chronic inflammation restricts blood flow arteries and increases right hear pressures. PAH is also seen in SHIV-infected macaques and was confirmed by necropsy findings of intimal thickening in the pulmonary vasculature. One new approach to PAH treatment uses the CCR5-blocking drug Maraviroc that was therapeutic in SHIV+ animals (Kelly, et. al, 2014). This finding supports a view that PAH is driven by chronic inflammation but does not explain the reasons for increased PAH in patients with HIV. We postulate that HIV-mediated depletion and dysregulation of T cells impairs a critical mechanism for the control of chrnic inflammation. Normally,  T cells provide costimulation to NK that increases their potency s cytotoxic effectors against dendritic cells (DC). In the absence of normal  T cell functio, NK do not receive critical costimulation, their capacity for eliminating DC is lost and with it, contrl of inflammation is impaired. Our strategy for treating PAH is to use two clinically approved drugs, zoledronic acid and IL2, that together will activate and expand the costimulatory  T cells By restoring normal  T cells function, we reconstitute the capacity for NK costimulation, DC killing and control of inflammation. Because of high PAH incidence and a proven therapeutic effect of Maraviroc, the SHIV-infected macaque is an ideal model for testing new therapeutic strategies including the direct activation of  T cells to resolve chronic inflammation. Mutiple co-morbid conditions of HIV disease are believed to be related to an underlying chronic immune activation and inflammation. By developing a therapeutic intervention against PAH, we may identify a strategy that is generally useful for blocking chronic inflammation that will improve an extend the lives of patients with HIV.