Cardiovascular Risk of Antiretroviral Therapy Drugs in HIV

点击翻译按钮获取中文摘要

PROJECT SUMMARY Although antiretroviral therapy drugs (ART) have prevented HIV propagation and increased life expectancy of people with HIV (PWH), the rate of sudden death in this population is 2-4-times higher than people without HIV. Autopsies have revealed cardiac fibrosis in half of this HIV patient population, a likely etiology for sudden death. The protease inhibitor class ART (PI-ART) is linked to cardiovascular risk in PWH, and it is plausible that ART can exacerbate the risk by inducing cardiac fibrosis. Our long-term goals are to determine the mechanism and the impact of ART-induced cardiac fibrosis in PWH, and to explore preventive strategies. Transforming growth factor β1 (TGFβ1) is a strong profibrotic cytokine and platelets contain ~100 times more TGFβ1 than other cells and are a major source of plasma TGFβ1 contributing to organ fibrosis. Higher plasma TGFβ1 levels and cardiac fibrosis are observed in HIV+ individuals, but whether ART further increases plasma TGFβ1 and cardiac fibrosis in PWH is not clear. In pilot studies, we observed that newer ART regimens, including PI-boosted dose of ritonavir (RTV) and tenofovir, activated platelets to release TGFβ1, which can be blocked by Ceefourin-1, a specific inhibitor of MRP4, a membrane transporter highly expressed in platelets from HIV patients. Injection of a PI-boosted dose of RTV in transgenic Tg26 HIV mice (which exhibit multiple HIV-associated comorbidities) increased cardiac fibrosis and diastolic dysfunction associated with the accumulation of CD206+ cells expressing αSMA in the heart, presumably macrophages. These results led to our central hypothesis that ART may activate platelets to release TGFβ1 via MRP4, which stimulates macrophages to undergo mesenchymal transition, inducing cardiac fibrosis. The objective of this application is to determine the mechanism by which different classes of ART induce platelet TGFβ1 release and identify the cell types to which TGFβ1 signals, leading to cardiac fibrosis. The following Specific Aims will address the objective: 1) Screen a panel of different classes of ART, alone and in combination, for induction of platelet release of TGFβ1 and identify the mechanisms of this process; 2) Determine whether contemporary ART-mediated TGFβ1 release via MRP4 induces cardiac fibrosis in vivo; 3) Determine whether TGFβ1 signaling in macrophages leads to mesenchymal transition and cardiac fibrosis. Our studies will clarify the mechanism of ART-induced TGFβ1 release from platelets and the cell types on which TGFβ1 signals, leading to cardiac fibrosis. We will use innovative techniques to evaluate platelet activation, measure plasma TGFβ1 levels, and assess cellular signaling and cardiac fibrosis in two murine models of HIV. Furthermore, our research will explore the translational potential for mitigating ART-induced cardiac fibrosis in HIV mice with anti-TGFβ1 and anti-fibrotic agents, such as Galunisertib or Pirfenidone. Our studies may also elucidate whether TGFβ1 could be a potential biomarker of underlying organ fibrosis in PWH. It may also lay the foundation for better mechanistic understanding and novel strategies for preventing comorbidities in PWH and fibrosis in other infectious diseases.