Wenyu Lin1, Ethan Weinberg1, Andrew Tai1, Lee Peng1, Mark Brockman1, Run-Xuan Shao1, Raymond Chung1
1 Massachusetts General Hospital, Harvard Medical School, Boston, USA
Background/Aims : HIV co-infection increases HCV-related hepatic fibrosis progression, HCV persistence, and decreases response rates to interferon-based anti-HCV therapy. We explored the possibility that circulating HIV and/or its proteins contribute to HCV pathogenesis through engagement of extracellular co-receptors on hepatocytes by using HCV replicon and infectious JFH1 models.
Methods : Inactivated HIV and recombinant HIV proteins were incubated with HCV replicon (a genotype 1b full-length HCV RNA and co-expresses Renilla luciferase) or infectious HCV JFH1 cells. TGF-β1 levels were measured by using human TGF-beta 1 ELISA Kit. To verify the dependence of HIV’s effects on HCV on gp120 binding to its cognate coreceptors, neutralizing antibody to CCR5 or CXCR4 were also tested.
Results : We found that inactivated HIV or gp120 increases HCV replication and enhances HCV-regulated TGF-β1 expression in both a replicon and an infectious model of HCV. HIV and gp120 enhancement on HCV replication is neutralized by antibodies to CCR5 or CXCR4. We found that human TGF-β1 also enhanced HCV replication. HIV’s effect on HCV replication was blocked by a neutralizing antibody to TGF-β1, indicating that its effects on HCV replication are TGF-β1 dependent.
Conclusions : HIV and gp120 has a proviral effect on HCV replication that is dependent on co-receptor engagement. HIV and gp120 appear to promote HCV replication through upregulating TGF-β1 in HCV-infected hepatocytes. These results implicate an effect of circulating HIV on innate antiviral immunity to HCV, and suggest a novel mechanism by which HIV not only enhances HCV replication but also contributes to hepatic fibrosis progression.