Abstract Body: Background: Despite highly active antiretroviral therapy (ART), HIV-associated cardiovascular disease and accelerated aging cause increased mortality in people living with HIV/AIDS (PLWHA). Nef protein has been detected in HIV patients even with ART therapy. We hypothesized that the Nef protein may compromise heart function and accelerate aging by dysregulation of autophagy.
Methods: We generated a Nef transgenic (Nef-TG) mouse model by cloning the HIV-Nef gene in the CAG-Lox-CAT vector. We used Western blotting to determine protein expression in cardiac tissue. Heart function was evaluated by echocardiography. Nef protein function was also determined by plasmid DNA transfection in the HEK293 cells.
Results: Nef-TG mouse shows cardiac dysfunction, increased cardiac fibrosis, and early mortality. Expression of autophagy marker LC3II was significantly decreased in the heart of Nef-TG mice. The data suggest Nef inhibits autophagy in the cell. Mechanistically, we found that senescence-associated markers p21, Bcl2, and Beclin1 levels significantly increased in Nef-TG mice's hearts, which may negatively regulate heart function and promote aging.
Conclusion: Our new Nef-TG mouse model revealed the cause of HIV-associated aging in PLWHA. Our mouse model can also be used to elucidate the role of Nef protein on other organ systems and test novel therapeutics for HIV.