Eui-Cheol Shin

Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection

IFN-gamma is known as the initial and primary inducer of immunoproteasomes during viral infections. We now report that type I IFN induced the transcription and translation of immunoproteasome subunits, their incorporation into the proteasome complex, and the generation of an immunoproteasome-dependent CD8 T cell epitope in vitro and provide in vivo evidence that this mechanism occurs prior to IFN-gamma responses at the site of viral infection. Type I IFN-mediated generation of immunoproteasomes was initiated by either poly(I:C) or HCV RNA in human hepatoma cells and was inhibited by neutralization of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in immunoproteasome subunit mRNA preceded intrahepatic IFN-gamma responses by several weeks, instead coinciding with intrahepatic type I IFN responses. Thus, viral RNA-induced innate immune responses regulate the antigen-processing machinery, which occurs prior to the detection of IFN-gamma at the site of infection. This mechanism may contribute to the high effectiveness (95%) of type I IFN-based therapies if administered early during HCV infection.

Private aspects of heterologous immunity

Clinical manifestations of viral infections are highly variable, both in type and severity, among individual patients. Differences in host genetics and in dose and route of infection contribute to this variability but do not fully explain it. New studies now show that each subjects history of past infections individualizes the memory T cell pool. Private T cell receptor specificities of these preexisting memory T cell populations influence both disease severity and outcome of subsequent, unrelated virus infections.

Liver-Directed Gamma Interferon Gene Delivery in Chronic Hepatitis C

ABSTRACT Gamma interferon (IFN-γ) has been shown to inhibit replication of subgenomic and genomic hepatitis C virus (HCV) RNAs in vitro and to noncytolytically suppress hepatitis B virus (HBV) replication in vivo. IFN-γ is also known for its immunomodulatory effects and as a marker of a successful cellular immune response to HCV. Therapeutic expression of IFN-γ in the liver may therefore facilitate resolution of chronic hepatitis C, an infection that is rarely resolved spontaneously. To analyze immunomodulatory and antiviral effects of liver-specific IFN-γ expression in vivo, we intravenously injected two persistently HCV-infected chimpanzees twice with a recombinant, replication-deficient HBV vector and subsequently with a recombinant adenoviral vector. These vectors expressed human IFN-γ under control of HBV- and liver-specific promoters, respectively. Gene transfer resulted in a transient increase of intrahepatic IFN-γ mRNA, without increase in serum alanine aminotransferase levels. Ex vivo analysis of peripheral blood lymphocytes demonstrated enhanced CD16 expression on T cells and upregulation of the liver-homing marker CXCR3. Moreover, an increased frequency of HCV-specific T cells was detected ex vivo in the peripheral blood and in vitro in liver biopsy-derived, antigen-nonspecifically expanded T-cell lines. None of these immunologic effects were observed in the third chimpanzee injected with an HBV control vector. Despite these immunologic effects of the experimental vector, however, IFN-γ gene transfer did not result in a significant and long-lasting decrease of HCV titers. In conclusion, liver-directed IFN-γ gene delivery resulted in HCV-specific and nonspecific activation of cellular immune responses but did not result in effective control of HCV replication.

The kinetics of hepatitis C virus-specific CD8 T-cell responses in the blood mirror those in the liver in acute hepatitis C virus infection.

ABSTRACT Peripheral blood T-cell responses are used as biomarkers in hepatitis C virus (HCV) vaccine trials. However, it is not clear how T-cell responses in the blood correlate with those in the liver, the infection site. By studying serial liver and blood samples of five vaccinated and five mock-vaccinated control chimpanzees during acute HCV infection, we demonstrate a correlation between HCV-specific CD8 T-cell responses in the blood and molecular and functional markers of T-cell responses in the liver. Thus, HCV-specific CD8 T-cell responses in the blood are valid markers for intrahepatic T-cell activity.