My award title is HIV-INDUCED 5-LIPOXYGENASE: ROLE IN HIV-RELATED PULMONARY ATERIAL HYPERTENSION. My research aim is to determine whether HIV-1 increases the susceptibility of infected individuals to develop the non-infectious pulmonary vasculature disorders such as pulmonary arterial hypertension. In the HIV-1-infected population, HIV-related pulmonary arterial hypertension (HIV-PAH) represents a serious and increasingly diagnosed health risk. Both PAH of the general population and HIV-PAH is characterized by increased vasoconstriction and vascular remodeling leading to a sustained increase in pulmonary arterial pressures. However, PAH in HIV-1 sufferers is several thousand times more prevalent and progresses more rapidly than PAH in the general population. Previous studies investigating the association between HIV-1 and PAH have found that HIV-PAH disease severity is unrelated to immune dysfunction and HIV-PAH development and progression may be linked to HIV-1 associated disease mediators, such as HIV-1 proteins. We have found that HIV-1 transgenic rats and HIV-1-treated co-cultures containing human pulmonary artery endothelial cells (HPAEC) and peripheral blood mononuclear cells (PBMC) demonstrate striking increases in arachidonate 5-lipoxygenase (ALOX5) mRNA expression. ALOX5 is the enzyme that catalyzes the production of the leukotrienes (LT) from arachidonic acid. These LT include LTB4 and the potent vasoconstrictors, LTC4, LTD4 and LTE4. We believe HIV-induced increases in ALOX5 expression could yield elevated LT levels and potentially contribute to PAH progression, a disorder characterized by pulmonary vasoconstriction and vascular remodeling. In this study, we aim to 1) determine the HIV-1 protein(s) that mediate increases in ALOX5 expression and activity and 2) indentify the role of ALOX5 in HIV-related PAH. We will employ both a cell culture and a HIV-1 transgenic (Tg) rat model to accomplish these aims. Human pulmonary artery endothelial cells will be cultured in the presence or absence of HIV-1 proteins for varying exposure times. Transcription, protein expression and leukotriene production will then be assessed. Also, we will assess the role of ALOX5 in HIV-PAH progression by administering the ALOX5 inhibitor, Zileuton to HIV-1 Tg rats exposed to hypoxic conditions. Successful completion of these objectives will lead to a better understanding of HIV-PAH and may yield future therapies for HIV-PAH sufferers and patients of other pulmonary vascular disorders.