Impact of HIV co-infections and comorbidities on circadian rhythm in the liver

Project Summary HIV-associated comorbidities, co-infections, and complications (CCCs) can exacerbate the health burden in people living with HIV (PLWH). Using innovative cell culture and in vivo systems, this application focuses on HIV-related pathogenesis in the liver and the establishment of a new area of HIV research that combines studies of the circadian rhythm in the context of HIV/HBV co-infections and other liver-related diseases such as fatty liver disease. Understanding the unique biological and metabolic processes that take place in PLWH with HIV- related CCCs may lead to highly impactful research findings and treatments. The main hypothesis of this proposal is that disruption of circadian clock genes, pathways, and functions may impact HIV-related CCCs. Disruption of circadian rhythm can alter the susceptibility to gut permeability to HIV and can further lead to complications in the liver. In addition, viral hepatitis, and specifically chronic HBV infection in PLWH poses a serious health burden as it accelerates the progression to liver cirrhosis and liver cancer with mechanisms that are still not well understood. Moreover, non-alcoholic fatty liver disease (NAFLD) is a complex disease which is impacted by circadian metabolic genes and pathways with detrimental consequences for liver pathogenesis in PLWH. Finally, drug metabolism takes place in the liver and metabolism of HIV antivirals is dependent on circadian regulation. The proposed studies will use state-of-the art technologies and physiologically-relevant cell culture and in vivo systems under normal or abnormal circadian conditions for HIV/HBV co-infection and fatty liver studies with the premise to yield highly impactful findings in HIV-related pathogenesis in the liver.