Abstract Body: Introduction: Cardiovascular diseases remain one of the leading causes of death worldwide. Modern antiretroviral therapy reduces the viral load to an undetectable level, and people living with HIV/AIDS (PLWHA) show higher life expectancy. However, persistent viral infection causes several comorbidities in PLWHA, and cardiovascular disease is one of the major causes of mortality and heart failure in HIV carriers. Nef protein is one of the virulent factors of HIV and can be detected in circulation as well as in the heart of HIV patients undergoing therapy. However, its impact at the organ level is not clear yet. In our previous study, we found that the Nef protein in a transgenic murine model causes inhibition of autophagy and leads to heart failure and premature death. However, its impact on cellular metabolism is not clear. To further understand the impact of Nef protein on cellular metabolism, we conducted a metabolic study in the Nef transgenic mice.

Method: We determined the level of nicotinamide adenine dinucleotide (NAD) and its synthesizing enzymes in the heart tissue of Nef-TG mice. Further, we used NAD precursor NMN to restore the cellular NAD level and determined its efficacy in the reduction of Nef-induced pathological disorders in the heart. Heart function was determined by echocardiography, and histological staining was conducted using H&E and Masson’s trichrome staining.

Result: Our metabolic study with cardiac tissue found that Nef expression reduces salvage pathway-mediated NAD production through inhibition of the rate-limiting enzyme NAMPT. Further, as our study found decreased levels of NAD in the heart of Nef TG mice, we explored whether cellular NAD+ replenishment can be a potential therapeutic target for HIV-associated cardiovascular disease. Interestingly, our study found that NMN treatment can improve cellular autophagy, reduce the senescence marker Bcl2, and suppress fibrosis in the heart.

Conclusions: Overall, our study suggests that HIV protein Nef promotes cardiovascular disease through the inhibition of autophagy, senescence, and reduction of cellular metabolites, and NMN can be a viable therapy option for the treatment of HIV-associated metabolic disorders and comorbidities.