Novel mechanisms of HIV-associated pulmonary vascular disease

PROJECT SUMMARY Thanks to the advent of combination antiretroviral therapy (cART), life expectancy has dramatically increased in people with HIV (PWH) and the spectrum of diseases related to HIV has shifted towards non-infectious chronic illnesses including cardiopulmonary disorders. Pulmonary vascular disease (PVD) is amongst the most

devastating cardiovascular complications of HIV. However, the etiopathology of pulmonary vascular remodeling, the critical structural alteration and pathological feature for PVD, 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 PVD. We provide novel exciting preliminary data in two mouse models of HIV supporting a role for CD4+ T Cells, HIV-Tat, and Podocan-like protein 1 (Podnl1) in PVD. We demonstrate that expression of HIV-derived proteins in Tg26 mice promotes PVD as shown by remodeled pulmonary arteries (PAs), increased

right ventricular systolic pressure and right ventricle hypertrophy, decreased pulmonary artery acceleration time (PAAT) and ratio of PAAT/pulmonary ejection time, as well as increased circulating Interleukin-1α (IL-1α) levels in male and female mice. We also report that these cardiopulmonary alterations are exacerbated with aging.

Remarkably, we show that bone marrow transplant (BMT) from Tg26 to wild type (WT) mice fully recapitulate the cardiopulmonary phenotype of Tg26 mice, which supports a role for viral proteins derived from hematopoietic cells in PVD. Using RNA Seq analysis, we identified a new marker of PVD, Podnl1. Its levels are increased in

the lungs of both intact and BMT Tg26 mice, but more importantly in the lungs of PWH on cART. We demonstrated that overexpression of Podnl1 in vascular smooth muscle cells (VSMCs) increases collagen levels and that of PCNA, a marker of cell proliferation. Using a newly developed “T cell- blood vessel” co-culture system,

we show that exposure of discarded human aorta and pulmonary artery specimens to Tg26 T cells elevate Podnl1 expression. Remarkably, we report that HIV-Tat is the only viral protein detectable in peripheral blood mononuclear cells (PBMCs) obtained from PWH on cART and show that chronic treatment of mice with Tat

reproduces the cardiopulmonary complications of intact and BMT Tg26 mice. Strikingly, we provide preliminary evidence of high IL-1α levels in PBMCs from PWH and found higher IL-1α levels in CD4+ than in CD8+ T cells isolated from Tg26 mice. Together, these exciting and novel findings form the core hypothesis of this proposal

that CD4+ T Cells expressing Tat promote PVD via IL1α-induced, Podnl1-mediated pulmonary artery remodeling. We will test this hypothesis in three aims. In aim 1, we will test whether HIV-encoded proteins accelerate PVD via Podnl1-dependent mechanisms. In aim 2, we will investigate whether HIV-associated PVD

involves CD4+ T cell-mediated, IL-1α-induced PVD, while aim 3 will test the hypothesis that HIV-derived Tat protein promotes Podnl1 production and mediates the development of HIV-PVD. We anticipate that this proposal will lead to the identification of new therapeutic targets for the prevention of HIV-associated PVD.