Abstract
Background & AimsPatients coinfected with HIV-1 and HCV develop more rapid liver fibrosis than patients monoinfected with HCV. HIV RNA levels correlate with fibrosis progression implicating HIV directly in the fibrotic process. While activated hepatic stellate cells (HSCs) express the 2 major HIV chemokine coreceptors, CXCR4 and CCR5, little is known about the pro-fibrogenic effects of the HIV-1 envelope protein, gp120, on HSCs. We therefore examined the in vitro impact of X4 gp120 on HSC activation, collagen I expression, and underlying signaling pathways and examined the in vivo expression of gp120 in HIV/HCV coinfected livers.MethodsPrimary human HSCs and LX-2 cells, a human HSC line, were challenged with X4 gp120 and expression of fibrogenic markers assessed by qRT-PCR and Western blot +/− either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody. Downstream intracellular signaling pathways were evaluated with Western blot and pre-treatment with specific pathway inhibitors. Gp120 immunostaining was performed on HIV/HCV coinfected liver biopsies.ResultsX4 gp 120 significantly increased expression of alpha-smooth muscle actin (a-SMA) and collagen I in HSCs which was blocked by pre-incubation with either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody. Furthermore, X4 gp120 promoted Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and pretreatment with an ERK inhibitor attenuated HSC activation and collagen I expression. Sinusoidal staining for gp120 was evident in HIV/HCV coinfected livers.ConclusionsX4 HIV-1 gp120 is pro-fibrogenic through its interactions with CXCR4 on activated HSCs. The availability of small molecule inhibitors to CXCR4 make this a potential anti-fibrotic target in HIV/HCV coinfected patients.
Highlights
HIV prevalence in the US is increasing due to a combination of the stable incidence of HIV and longer life expectancy due to effective antiretroviral therapies (ART) [1]
X4 gp 120 significantly increased expression of alpha-smooth muscle actin (a-SMA) and collagen I in hepatic stellate cells (HSCs) which was blocked by pre-incubation with either CXCR4-targeted shRNA or anti-CXCR4 neutralizing antibody
X4 HIV-1 gp120 is pro-fibrogenic through its interactions with CXCR4 on activated HSCs
Summary
HIV prevalence in the US is increasing due to a combination of the stable incidence of HIV (estimated at 53,600 new cases per year in 2006) and longer life expectancy due to effective antiretroviral therapies (ART) [1]. As HIV patients continue to live longer in the setting of effective ART, liver disease has become the leading cause of non-AIDS related mortality [2]. Due to shared routes of transmission, HCV and HBV are common in HIV-infected patients though ethanol-induced liver disease is prevalent. While immune dysregulation in the setting of HIV infection may play a role in accelerating liver fibrosis from HCV, recent studies suggest faster fibrosis progression in HIV/HCV coinfected patients despite effective anti-retroviral therapy [7]. While separating the impact of decreased CD4 count from HIV RNA levels is difficult, cohort studies suggest independent effects of HIV RNA on fibrosis progression [1,8,9]. A dose-dependent effect of HIV RNA levels on fibrosis progression rates was observed, further implicating the virus in enhanced liver fibrogenesis [8]. We examined the in vitro impact of X4 gp120 on HSC activation, collagen I expression, and underlying signaling pathways and examined the in vivo expression of gp120 in HIV/HCV coinfected livers
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