HIV co-infection accelerates HCV- and HBV-related liver disease progression and represents a major public health problem. Chronic inflammation, the hallmark of chronic viral hepatitis, is characterized by infiltration of inflammatory cell populations, including activated macrophages, which are also important reservoirs for HIV. Activated hepatic macrophages polarize into M1/pro-inflammatory or M2/profibrotic phenotypes that can activate hepatic stellate cells, leading to fibrosis. Circulating levels of soluble CD163 (sCD163), a characteristic M2 marker, have been strongly associated with fibrosis in chronic HCV and HBV. Importantly, high levels of sCD163 are also observed in HIV infection. Our preliminary data demonstrate significantly greater increase of sCD163 in HIV/HCV co-infection compared to HIV or HCV alone and that sCD163 levels significantly correlate with liver fibrosis stage. We also observed that successful anti-retroviral therapy in HIV/HCV coinfection significantly decreased sCD163 levels. We have also shown that HIV and HCV together cooperatively induce the M2 phenotype in vitro. We hypothesize that HIV directly and indirectly contributes to the expansion of profibrotic M2 macrophages, which in turn exacerbate liver fibrosis in the setting of viral hepatitis. Intriguingl, macrophages expressing epidermal growth factor receptor (EGFR) have been recently reported to play an essential role in promoting hepatocellular carcinoma via IL-6 dependent mechanisms. Since IL-6 can induce M2 polarization and HIV has been shown to enhance EGFR signaling in infected cells, we further hypothesize that EGF signaling mediates HIV's contribution to generation of the profibrogenic state. We propose to further explore these hypotheses through the following aims: (1) Determine the association of HIV infection with M2 markers in patients with and without chronic viral liver disease. Using liver tissue from patients with chronic HCV and HBV, we will assess whether each condition is associated with enhanced intrahepatic M2 phenotype in HIV coinfection. We will also assess whether HIV monoinfection is associated with the M2 hepatic profile by evaluating liver tissue from HIV monoinfected persons without evidence of liver disease and comparing to normal liver tissue. (2) Perform mechanistic studies whose goal is to define how HIV promotes expansion of profibrotic macrophage polarization. We will specifically evaluate HIV's effects on liver macrophages using RNA-Seq, and will assess the contribution of EGFR signaling to HIV's effects on the macrophage population by performing inhibitor studies. We will also assess HIV's promotion of fibrogenesis using stellate cell cocultures. (3) Evaluate the effects of antiretroviral suppression of HIV on hepatic macrophages in vitro and in vivo. The latter studies will be carried out using hepatic fine needle aspirates frm HIV/HCV coinfected persons undergoing initiation of ART. We will test the hypothesis that successful HIV suppression partially but does not fully reverse the effect of HIV on alteration of the profibrogenic macrophage phenotype. These studies will shed great light on the contribution of the macrophage to HIV-associated liver fibrosis progression.
HIV-1 infection accelerates the natural history of chronic liver diseases, including chronic hepatitis C and B. There is emerging evidence to support the concept that by infecting the macrophage, a key liver cell that contributes to hepatic fibrosis, that HIV-1 is contributing substantively to progression of liver disease. This proposal will explore the basis by which HIV-1 affects these liver macrophages to alter the course of chronic liver conditions, and in so doing suggest a new target for interrupting liver fibrosis
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| Duan, Xiaoqiong; Li, Shilin; Holmes, Jacinta A et al. (2018) MicroRNA 130a Regulates both Hepatitis C Virus and Hepatitis B Virus Replication through a Central Metabolic Pathway. J Virol 92: |
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| Salloum, Shadi; Holmes, Jacinta A; Jindal, Rohit et al. (2016) Exposure to human immunodeficiency virus/hepatitis C virus in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types. Hepatology 64:1951-1968 |
| Bility, Moses T; Nio, Kouki; Li, Feng et al. (2016) Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation. Sci Rep 6:39520 |
