PROJECT SUMMARY Virological and Immune mechanisms of HIV-enhanced liver diseases (HELD) Liver diseases caused by HIV-1 infection under cART or HAART without HBV/HCV co-infection are generally understudied and pose a serious health problem because half of the estimated 38 million HIV- infected people are currently under cART. HIV-induced inflammation is not completely resolved during cART and may contribute to the increased risk of liver diseases. The lack of small animal models to investigate HIV- enhanced liver diseases (HELD) impedes our ability to dissect the virological and immunological mechanisms, and to efficiently test new therapeutics. My lab has created or improved, over many iterations, humanized mouse models that can be engrafted with a functional human immune system and human liver cells such as HepSC. Based on our recent findings, the Hu-HSC/Hep model develops HELD during persistent HIV/cART, which will allow us to systematically characterize the mechanisms of HELD. The long-term goals of the project are to elucidate the viral and immunologic mechanisms of HIV– enhanced human liver diseases (HELD) and to develop novel therapeutics (IFNAR blocking antibody/bAb and M2 macrophage inhibitors) in the novel humanized mouse model with human immune and human hepatic stellate cells (Hu-HSC/HepSC mice). Specifically, we will achieve the following milestones related to HIV- enhanced liver diseases: (i) establishment/optimization of HIV-enhanced liver disease (HELD) models in Hu- HSC/HepSC mice during HIV/cART; (ii) elucidation of viral and immunological mechanisms by which HIV-1 induces M2 pathogenic macrophages to exacerbate liver diseases; (iii) defining the role of HIV-induced IFN-I and M2 macrophages in HIV-enhanced liver fibrosis; and (iv) development of the IFNAR bAb and M2 inhibitors to treat HIV/cART associated liver diseases. Findings from the project will have a significant impact on understanding HIV-induced mechanisms in promoting liver diseases and on discovering novel targets for developing novel therapeutics.