HIV-derived proteins contribute to the development of pulmonary arterial hypertension in mice

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening lung disease caused by remodeling of pulmonary vascular walls which is associated with a sustained elevation in pulmonary arterial pressure leading to RV failure and ultimately death. HIV infection increases the risk of developing severe PAH and HIV-associated PAH has a poor prognosis with elevated mortality. Despite significant effort to understand its pathophysiology, the identification of signaling pathways involved in HIV-mediated onset and progression of PAH remains scarce. The aim of the present study is to unravel the mechanistic links between HIV and PAH and to investigate how HIV-derived proteins contribute to the pathological processes of pulmonary vascular remodeling (PVR) of PAH and right ventricle (RV) hypertrophy. Three different HIV mouse models have been used to answer these questions. Our results showed that transgenic HIV-1 Tg26 mice, which mimics people living with HIV (PLWH) with low viremia and without progression to AIDS, exhibit increased right ventricular systolic pressure (RVSP), Fulton-index and thickness of pulmonary arterial wall indicating PVR and RV hypertrophy in these mice. More importantly, transfer of bone marrow (BMT) from Tg26 to wild-type (WT) mice and chronic treatment with HIV-encoded Tat protein induce development of PAH and RV hypertrophy in WT mice indicating that HIV-derived proteins contribute to the pathogenesis of PAH in mouse models of HIV. In order to explore signaling pathways involved in the HIV-related PAH, RNA sequencing and qPCR were performed using lung samples from control/Tg26 mice and BMT mice. We found increased expression of the proliferative marker Ki67 in Tg26 lung endothelial cells (EC). In Tg26 lung vascular smooth muscle cells (VSMC), markers of contractile SMC phenotype (SM22, SM MHC) were decreased while markers for synthetic SMC phenotype (Vimentin, Rbp-1) were upregulated suggesting increased EC proliferation and SMC de-differentiation in Tg26 mice. Moreover, we identified ten genes which expression levels were up/ downregulated in the lungs of Tg26 mice which can potentially contribute to the development of HIV-associated PAH. In conclusion, we have established a novel model of HIV, the BMT Tg26 to WT mice, to study the contribution of immune cell derived viral proteins to PAH and demonstrated that at least one viral protein, the HIV-Tat, is involved in the development of PAH and RV hypertrophy associated with HIV. Additional studies are needed to further elucidate the role of these signaling mechanisms in HIV-induced PAH in order to develop effective therapy for the prevention and treatment of this lung disorder. Supported by NIH NHLBI 1R01HL147639 (EBdC) and Augusta University IGP IGPP00030 (LK). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.