Alcohol metabolism potentiates HIV-induced lung and liver multimorbidity via inter-organ crosstalk

PROJECT SUMMARY/ABSTRACT Human immunodeficiency virus (HIV) / acquired immune deficiency syndrome (AIDS) remains one of the most critical public health problems in the 21st century, with more than 39 million global infections. Antiretroviral therapy (ART) significantly suppresses viremia, leading to a decline in AIDS-related mortality. Conversely, there

are emerging concerns of multimorbidity (i.e., co-occurrence of ≥2 chronic diseases) despite ART-induced longevity. Multimorbidity significantly impacts the health quality of people living with HIV (PLWH) and poses a substantial financial burden on the healthcare system. While HIV drives multimorbidity, alcohol, consumed by

more than 50% of PLWH, promotes HIV-associated multimorbidity. Alcohol mediates multimorbidity by promoting organ-organ crosstalk via extracellular vesicles (EVs) and inflammatory mediators. The direct effects of HIV and alcohol on the lungs and the liver have been demonstrated; however, there is a gap in knowledge about whether

HIV- and alcohol-induced lung and liver injuries are regulated by EV-mediated crosstalk. The objectives of the studies outlined in this proposal are to investigate the triggering effects of alcohol metabolism and HIV on the secretion of lung-derived EVs and the role of these EVs in amplifying the release of liver cytokines into circulation

to induce lung injury. To achieve these objectives, during the K99 phase of this award, the PI will determine how alcohol enhances EV release in HIV-infected alveolar macrophages, AMs (Aim 1). Then, the roles of EVs secreted by alcohol and HIV-stressed AMs in the depletion of alveolar epithelial cells and barrier dysfunction will

be examined (Aim 2). During the R00 phase, the PI will examine the contribution of EVs to lung-liver crosstalk driven by HIV infection and EtOH consumption in vivo (Aim 3). Successful completion of these studies will identify molecular targets that will make it possible to concurrently address both lung and liver multimorbidity among

PLWH who misuse alcohol. The PI’s focus on alcohol research began during his predoctoral training when he investigated the contribution of the hepatocyte-hepatic stellate cell axis to alcohol—and HIV-induced liver injury via the NRSA NIAAA F31 funding mechanism. The PI acquired additional expertise with numerous molecular techniques during his

postdoctoral training in the laboratories of Dr. Yeligar and Koval, when exploring the contribution of alcohol and HIV to AM immune dysfunction and alveolar barrier impairment. The support from this MOSAIC K99/R00 grant will provide the PI an outstanding opportunity to expand and consolidate his experimental and laboratory skills, collect critical preliminary data for subsequent grant

applications, present research findings at national meetings, and support his career goal to become an independent investigator. Thus, this MOSAIC K99/R00 application provides an excellent opportunity to advance the career of the PI in developing his independent research program with a focus on HIV- and alcohol-induced

inter-organ crosstalk during the R00 phase.