Mechanisms of HIV-associated Hypertension

PROJECT SUMMARY Over the last few decades, the advent of combination antiretroviral therapy has led to a profound suppression of HIV replication and dramatically increased life expectancy in people with HIV (PWH). As a consequence, the spectrum of diseases related to HIV has shifted from opportunistic AIDS-related disorders towards a premature

aging phenotype including an early onset of cardiovascular disease (CVD). CVD is now the leading cause of death in PWH, however, the etiopathology of the accelerated development of hypertension, the leading risk factor for CVD, has yet to be determined. Herein, we will test whether HIV derived proteins, which remain in

circulation despite cART and well-controlled viremia, contribute to the development of hypertension. We provide novel exciting preliminary data in the Tg26 mouse model of HIV supporting a role for T cell-derived HIV proteins and inflammation in vascular dysfunction, sympatho-activation, and hypertension. We demonstrate that

expression of HIV-derived proteins in Tg26 mice increases circulating Interleukin-1α (IL-1α), impairs endothelium-dependent relaxation, increases sympathetic activity, and induces hypertension in male and female mice. Remarkably, we show that transplant of bone marrow from Tg26 to wild-type (WT) mice recapitulates the

cardiovascular phenotype of intact Tg26 mice. Moreover, inhibition of T lymphocytes (T cells) activation restores blood pressure (BP) and sympatho-activation and improves endothelial function in Tg26 mice. Conversely, exposure of WT aortic rings to Tg26 T cells in a novel “T cells-vessel” co-culture system impairs endothelial

function and incubation with an anti-IL-1α antibody abrogates Tg26 T cell-mediated endothelial dysfunction. We also show that endothelial dysfunction involves increased expression of the NADPH oxidase homologue Nox1 and that deficiency in Nox1 protects against Tg26-induced hypertension and endothelial dysfunction. Strikingly,

we provide very preliminary evidence of higher IL-1α transcriptional levels in CD4+ T cells from PWH and show that aorta specimens discarded from PWH exhibit higher Nox1 expression than that from HIV- individuals. In addition, exposure of human aorta specimen to Tg26 T cells media elevates Nox1 expression. Finally, we report

that infusion of the viral protein Tat in mice impairs endothelial function via Nox1-dependent mechanism. Together, these exciting and novel findings inform the core hypothesis of this proposal: HIV Tat protein derived from CD4+ T cells induces hypertension via IL-1α and Nox1 dependent mechanisms. We will test this hypothesis

in three aims. In aim 1, we will test whether HIV-associated hypertension involves CD4+ T cell-mediated, IL-1α-induced endothelial dysfunction and sympatho-activation. In aim 2 we will investigate whether IL-1α accelerates vascular aging and promotes hypertension through Nox1 and senescence-mediated endothelial dysfunction,

while aim 3 will test the hypothesis that HIV-derived Tat protein promotes IL-1α-production from T cells and hypertension. We anticipate that this proposal will lead to the identification of the new therapeutic targets to prevent the accelerated development of CVD exhibited by people with HIV.