No abstract

The chemokine CXCL-8 (interleukin-8) is induced by many viruses, including hepatitis C virus (HCV).In the current study, we examined CXCL-8 levels in the context of acute and chronic HCV replication in vitro. Two different small interfering RNAs were used to silence CXCL-8 mRNA and protein expression in Huh7 and BB7 replicon cells. HCV RNA synthesis in BB7 cells was inhibited by CXCL-8 knockdown. Furthermore, antibody neutralization of endogenous CXCL-8 activity inhibited HCV replication, while addition of recombinant human CXCL-8 stimulated NS5A protein expression. Moreover, CXCL-8 protein levels correlated positively with HCV RNA levels in four independent subgenomic and genomic replicon lines (R ‫؍‬ 0.41, P ‫؍‬ 0.0013). However, CXCL-8 mRNA levels correlated inversely with CXCL-8 protein and HCV RNA levels in all replicon lines and in Huh7 cells. Transient replication assays with strongly permissive and weakly permissive Huh7 cells and three independent subgenomic replicons with various replicative capacities revealed that CXCL-8 protein levels were higher in weakly than in strongly permissive cells. The JFH-1 subgenomic replicon, which replicated to high levels in both strongly and weakly permissive Huh7 cells, induced CXCL-8 protein to high levels in both cell types. The data indicate that in the replicon system, CXCL-8 protein levels are positively associated with chronic HCV replication and that CXCL-8 removal inhibits HCV replication. During acute HCV replication, CXCL-8 production may be inhibitory to viruses with low replicative capacity. The data underscore the complex regulation of CXCL-8 mRNA and protein expression and further suggest that in addition to contributing to HCV pathology via proinflammatory actions, CXCL-8 may have opposing antiviral and proviral effects depending on the level of HCV replication, the cellular context, and whether the infection is acute or chronic.Infection with hepatitis C virus (HCV) is a serious medical issue. HCV is unique among hepatitis viruses in that the majority (Ͼ70%) of acutely infected individuals progress to chronic infection, resulting in an estimated 170 million infected individuals worldwide. Chronic HCV infection is thus a major cause of liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma (2).Cloned in 1989 (7), HCV encodes a single polyprotein precursor that is cleaved when expressed in cell culture into at least 10 proteins. The first third of the genome encodes the structural proteins that form the virion. They include the core protein, two envelope proteins (E1 and E2), and a small protein with ion channel functions (P7). An additional open reading frame in the core gene has recently been described, although the role of this protein in HCV replication and pathogenesis remains to be determined. Nonstructural proteins are derived from the remaining two-thirds of the polyprotein and include NS2, NS3 (a serine protease/helicase), NS4A, NS4B, NS5A, and NS5B (the RNA-dependent RNA polymerase). Despite extensive genetic and biochemica...

The data suggest that increased CXCL-8 gene expression in the context of HCV replication involves posttranscriptional events.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs), particularly nevirapine, have been associated with hepatotoxicity. We performed a retrospective study to determine the incidence of NNRTI hepatotoxicity in a group of HIV-infected patients from a New York City practice. These patients are predominantly homosexual white males. We also analyzed the effect of coinfection with hepatitis B (HBV) or hepatitis C (HCV) virus. In total, 272 patients received NNRTIS: 40 (15%) received delavirdine, 91 (33%) received efavirenz, and 141 (52%) received nevirapine. Of the patients with known hepatitis status, 18 of 190 (9%) were coinfected with HBV, and 24 of 205 were coinfected (12%) with HCV. The overall rate of grade 3 to 4 elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) was 3 of 272 (1.1%) and did not differ significantly among the three NNRTIs. HBV or HCV was not associated with a significant increase in AST or ALT elevations. We conclude that NNRTIs are relatively free from hepatotoxicity in this population, despite the presence of coinfection with HBV or HCV.