Combination antiretroviral therapy (cART) has been remarkably successful in combating opportunistic AIDS- related diseases and increasing life expectancy. However, cART has unexpectedly shifted the spectrum of disease burden towards an acceleration of cardiovascular diseases (CVD), including atherosclerosis, which is now the leading cause of mortality in HIV patients. Strikingly, contemporary cART regimens have also induced a drastic switch in the metabolic phenotype of HIV patients from a loss (lipoatrophy) to a pronounced gain in adiposity. Yet, increased adiposity does not further augment CVD risk in contemporary HIV patients, creating an obesity paradox in HIV-cART. A critical barrier to the prevention of CVD in HIV patients is our lack of understanding of the mechanisms whereby HIV and cART regulate adiposity and atherogenesis, and the role of adiposity in HIV-cART-associated vascular diseases. Herein, we provide exciting new preliminary data indicating that HIV viral infection promotes atherosclerosis in mice. We show that viral infection and lipoatrophy induce endothelial dysfunction by reducing leptin levels and leptin signaling in the vasculature. We find elevated expression of the oxidant generating enzyme Nox1 in blood vessels and show that ROS scavenging with tempol, or pharmacological inhibition of Nox1, restores endothelial function in our rodent models of HIV and lipoatrophy. In parallel, we report decreased leptin signaling and increased vascular inflammation in aortic sections from human HIV patients. Remarkably, chronic leptin treatment robustly improves endothelium-dependent relaxation in rodent models of HIV and lipoatrophy. Moreover, leptin markedly reduces Nox1 expression in aortae and blunts expression of pro-inflammation mediators. Strikingly, selective deletion of the leptin receptor in endothelial cells impairs endothelial function via a Nox1-dependent mechanism. Lastly, we show that viral infection increases TNF? which is a known positive regulator of energy expenditure. We also report that viral infection prevents diet-induced adipose tissue expansion, while the contemporary cART regimen Odefsey markedly increases body weight without inducing endothelial dysfunction in wild-type mice. Taken together, these exciting and novel findings inform the core hypothesis of this proposal: HIV promotes atherosclerosis by disrupting endothelial leptin signaling and augmenting Nox1 expression, which is opposed by contemporary cART regimens that preserve adiposity and leptin levels. We will test this hypothesis in the following specific aims: (1) Activation of endothelial leptin signaling protects against endothelial dysfunction in HIV-cART; (2) Contemporary cART regimens prevent the development of atherosclerosis in HIV mice via adipose-leptin mediated improvement in endothelial function and reduction in vascular immune cell infiltration; and (3) HIV and cART regulate body weight via TNF?-mediated control of energy expenditure. The expectation is to identify the molecular mechanisms whereby HIV and cART regulate adiposity and atherogenesis to identify new therapeutic avenue for the prevention and treatment of CVD- associated with HIV.

Public Health Relevance

Atherosclerosis-associated cardiovascular diseases are currently the leading cause of death in HIV patients under antiretroviral therapy. However, the molecular mechanisms predisposing HIV+ patients to atherosclerosis remain poorly defined and unstudied. The proposed study will combine the use of novel genetically engineered animal models with discarded human samples, cultured endothelial cells and pharmacological approaches to decipher the respective contribution of viral infection and antiretroviral therapy to the formation of atherosclerotic lesions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL147639-02
Application #
10077588
Study Section
HIV Comorbidities and Clinical Studies Study Section (HCCS)
Program Officer
Altekruse, Sean Fitzgerald
Project Start
2020-01-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Augusta University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912