Pulmonary arterial hypertension (PAH) involves pathological remodeling of the lung vasculature and frequently results in significant disability and death. Patients infected with HIV have a higher than expected incidence of PAH. This proposal will focus specifically on mechanisms through which viral gene products expressed in patients infected with HIV-1 predispose the host to develop PAH. In addition, this proposal will explore the modulatory effects of current highly active retroviral therapy (HAART) for the treatment of HIV-1 on these mechanisms. Tat is an essential regulatory protein responsible for transcriptional activation of HIV-1. Defining how Tat modulates endothelial cell function towards the development of PAH, alone or together with other peptide factors elevated in the serum of HIV+ patients, in vitro and in vivo, is a focus of this proposal. Importantly, patients infected with HIV are commonly co-infected with human herpesvirus-8 (HHV-8). HHV-8 is known to localize to the lung endothelium, is associated with both HIV-related pulmonary hypertension (HRPH) and idiopathic pulmonary artery hypertension (iPAH), and expresses a viral G-protein coupled receptor (vGPCR) that induces angioproliferative disease. The central hypothesis to be tested in this proposal is that HHV-8 vGPCR togther with Tat predispose an individual to develop HRPH. In keeping with the directives of this RFA, the approach will study the effects of HHV-8 vGPCR, Tat, and HAART on pulmonary vascular endothelial cells and smooth muscle cells derived from humans. The biological significance of findings from the in vitro studies will be evaluated in vivo using a murine hypobaric hypoxia model of PAH because hypoxic stress occurs in patients with AIDS. This proposal brings together the collaborative expertise of 4 NIH-funded investigators, with complementary skills and experience pertaining toangiogenesis, vascular biology, and pharmacology to address this important clinical malady. The experiments to address these Specific Aims will define the role of vGPCR, Tat and HAART drugs in the development of HRPR and advance our understanding of the pathogenesis of this fatal disease, which in turn will eventuate in more effective treatments for PAH.
