Abstract
Previous studies demonstrate that soluble HIV proteins impact both hepatocyte function and HCV replication in vitro. It has also been reported that HIV can productively infect hepatocytes. We therefore investigated the impact of HIV infection of hepatocytes on HCV expression. The Huh7.5JFH1 cell line that constitutively expresses infectious HCV was infected with the lab-adapted strains HIVNL4-3 or HIVYK-JRCSF. HCV expression was quantified via HCV core antigen ELISA, Western blot, and strand-specific real-time PCR for positive-sense and negative-sense HCV RNA. After HIVNL4-3 infection of Huh7.5JFH1 cells, positive-sense and negative-sense HCV RNA levels were elevated compared to HIV uninfected cells. Increased HCV RNA synthesis was also observed after infection of Huh7.5JFH1 cells with HIVYK-JRCSF. HIV-induced HCV core production was decreased in the presence of the anti-HIV drugs AZT, T20, and raltegravir, although these medications had a minimal effect on HCV expression in the absence of HIV. HCV core, NS3, and NS5A protein expression were increased after HIV infection of Huh7.5JFH1 cells. Chemically inactivated HIV had a minimal effect on HCV expression in Huh7.5JFH1 cells suggesting that ongoing viral replication was critical. These data demonstrate that HIV induces HCV RNA synthesis and protein production in vitro and complement previous in vivo reports that HCV RNA levels are elevated in individuals with HIV/HCV co-infection compared to those with HCV mono-infection. These findings suggest that HIV suppression may be a critical factor in controlling liver disease, particularly if the underlying liver disease is not treated.
Highlights
Since the introduction of highly active antiretroviral therapy (HAART), liver disease – frequently caused by hepatitis C virus (HCV) co-infection – has surpassed AIDS-defining illnesses as a major cause of morbidity and mortality in HIV-positive persons [1,2]
Such interactions may be mediated via 1) secreted HIV proteins that interact with HCV-infected hepatocytes, and/or 2) direct HIV
We examined the effects of HIV infection on HCV replication in Huh7.5JFH1 hepatocytes
Summary
Since the introduction of highly active antiretroviral therapy (HAART), liver disease – frequently caused by hepatitis C virus (HCV) co-infection – has surpassed AIDS-defining illnesses as a major cause of morbidity and mortality in HIV-positive persons [1,2]. Multiple clinical studies have clearly demonstrated that HIV co-infection results in increased HCV RNA levels, progressive liver disease, and decreased HCV treatment response rates (reviewed in [3,4]). HIV-positive patients with no evidence of viral hepatitis co-infection exhibit mild-tomoderate increases in liver enzyme levels [9,10,11]. Such interactions may be mediated via 1) secreted HIV proteins that interact with HCV-infected hepatocytes, and/or 2) direct HIV infection of HCV-infected hepatocytes. Until recently, in vitro systems to study the complete HCV life cycle were unavailable; our ability to explore HIV/HCV interactions were limited. The availability of distinct classes of anti-HIV agents that target viral entry, reverse transcription, integration, or infectious virion production allows for more detailed mechanistic studies of HIV-mediated HCV replication
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