Hepatic Transcriptome Analysis of Hepatitis C Virus Infection in Chimpanzees Defines Unique Gene Expression Patterns Associated with Viral Clearance

Abstract

Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV) infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3) and cytotoxic granule-associated RNA binding protein (TIA1), associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a “danger signal” leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection.

Gene-expression profiling in vaccine therapy and immunotherapy for cancer

“…In particular Saint-Mezard et al (51) , by comparing three independent microarray data sets of kidney biopsies, identified IRF-1 as the main transcription factors that regulated the 70 genes consistently represented during acute allograft rejection episode. Imanguli et al (92) , observed similar patterns by studying biopsies of tissues suffering chronic graft versus host disease and similar patters where observed in the liver during clearance of HCV infection (93,94,95,96,97) . Recently similar signatures were observed in the destructive phases of acute cardiovascular events (98,99) , chronic obstructive pulmonary disease (100) and placental villitis (101) .…”

Identification of the transcripts associated with spontaneous HCV clearance in individuals co-infected with HIV and HCV

“…In the current study we could not detect any significant relationship between CC genotype and HCV clearance, because the CC genotype was found in four of the five clearance subjects and four of the eight chronically HCV infected subjects. The distribution of the genotypes in the infected subjects suggests that other factors beside the IL28B SNPs play a role in the spontaneous HCV clearance in the co-infected individuals [14, 18, 27]. However, the small sample size in our study also could explain our failure to detect an association between IL28B polymorphisms and HCV clearance.…”

“…Two studies have reported transcriptomes analysis of liver tissues of HCV infected chimpanzees with spontaneous viral clearance or chronic infection outcomes. Nanda et al [18] reported that early induction of the genes associated with cell proliferation and immune activation, especially interleukin binding factor 3 (ILF3) and cytotoxic granule associated RNA binding protein (TIA1), was associated with subsequent HCV clearance in infected chimpanzees. Suet et al [28] reported that cellular genes induced by IFN-γ and those involved in antigen processing/presentation and the adaptive immune response were associated with HCV clearance.…”

“…Various factors, such as gene polymorphisms in interleukin 28B ( IL28B) and IP-10 have been implicated in mediating host susceptibility/resistance to HCV infection and disease progression [14–17]. In HCV-infected chimpanzees, interleukin binding factor 3 (ILF3) and cytotoxic granule associated cRNA binding protein (TIA1), which are associated with robust T-cell responses, were highly induced in animals who cleared the virus [18]. However, these represent only a few of the many factors that are potentially involved in HCV clearance.…”

T-cell intracellular antigens in health and disease

“…This constitutes a primary response to eliminate infected hepatocytes. 104 Inflammation and immune processes Regarding the inflammatory processes, TIA1 and TIAR function as gene suppressors in arthritis. 105 Consequently, TIA-deficient mice develop arthritis.…”