Abstract Liver disease in patients with HIV infection remains a major public health problem despite effective combination antiretroviral therapy (cART), and cART does not fully reverse HIV-related immune activation. Monocyte and macrophage populations play a central role in inflammation and liver pathogenesis and are triggered during HIV, even in the absence of known causes of liver injury. Chronically activated monocytes/macrophages polarize to a spectrum of pro-inflammatory and anti-inflammatory states which contribute to hepatic fibrogenesis. Our preliminary study of the immune cell landscape in liver fine needles aspirates (FNAs) and corresponding peripheral blood mononuclear cells (PBMCs) from patients with HIV infection prior to and during the first 6- months of cART, uncovered 1) the presence of monocytic myeloid-derived suppressor cells (M-MDSC) that persist on cART despite virus control; and 2) increased serum levels of sCD5L, the soluble scavenger receptor secreted by macrophages, which does not decrease on cART. Both M-MDSCs and sCD5L are described to expand in inflammatory conditions, have anti-inflammatory effects, and recently have been shown to promote the anti-inflammatory/profibrotic macrophage phenotype. We have also observed similar findings in HCV infection and NASH. Together these findings may constitute a causative mechanism driving a profibrotic milieu, particularly in the liver. We hypothesize that HIV-induced M-MDSCs and CD5L remain upregulated on suppressive ART and contribute to a persistent profibrotic liver milieu. Using patient derived human material, we will test this hypothesis through the following aims: (1) Define the role of M-MDSCs in driving fibrogenesis in the setting of HIV infection. Using M-MDSCs from healthy donor PBMC pre/post exposure to HIV, we will assess whether HIV-induced M-MDSCs drive the profibrotic profile in macrophages and hepatic stellate cells (HSCs) and will explore contributory mechanisms using blocking/silencing functional assays. Additionally, to confirm whether M-MDSCs persist in suppressed HIV in vivo, we will comprehensively characterize the transcriptomic/proteomic single cell landscape in HIV patient PBMCs, pre-ART/at several timepoints of cART. (2) Define the role of CD5L in driving fibrogenesis in the setting of HIV infection. Using recombinant (r)CD5L we will determine whether this product promotes the profibrogenic profile in HIV-triggered healthy donor monocyte derived macrophages and M-MDSCs as well as in HIV-exposed primary HSCs and/or hepatocytes. Additionally, we will determine if plasma from HIV patients (pre/during cART) with or without CD5L blocking antibodies induces a profibrotic phenotype. (3) Determine how HIV impacts M-MDSC and CD5L function in the setting of co-existing liver disease. We will comparatively explore M-MDSCs and CD5L by single cell transcriptomics/proteomics in cohorts of patients with HIV, HIV/HCV, HIV/HBV and HIV/NASH in liver FNAs, and we will vali...