INTERFERON GAMMA AND CONTROL OF HCV REPLICATION

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The chimpanzee is the only available animal model for hepatitis C virus (HCV) infection. HCV persistents life-long in humans in approximately 70% of individuals infected. Chronic infection with this virus is the cause of serious long-term health problems that include liver disease and cancer. Indeed, most liver transplantations in the United States are the direct result of chronic liver disease caused by HCV. Approximately 2% of the world's population is infected with HCV, and it is therefore considered a significant global health problem. Currently, there are no vaccines available for this virus, and available therapy is toxic and ineffective in many. The mechanisms by which replication of HCV is controlled and eventually terminated by those individuals that are able to resolve infection remain unclear, however are of paramount importance both to the production of an effective vaccine for this pathogen, and to future development of effective therapies. In experiments in transgenic mouse models and the chimpanzee, it has been demonstrated that control of hepatitis B virus replication can be controlled by secretion of the cytokine IFN-gamma by immune cells (Guidotti and Chisari. Ann Rev Immunol 2001; 19: 65-89), rather than viral control requiring killing of infected cells by the immune system. Experiments using in vitro systems suggest that IFN-gamma could contribute to control of HCV replication (Frese et al Hepatology 2002; 35:694703; Lanford et al J Virol 2003; 77: 1092-1104). However this in vitro data does not necessarily reflect in vivo events. A single study has been carried out examining whether supplementation of IFN-gamma alters viral replication in chronic HCV infection (Shin et al. J Virol 2005; 79: 13412-30); however it is likely that both the infecting virus has escaped from HCV-specific responses and that persisting HCV-specific immune responses are defective by this stage of infection (Bowen and Walker. Nature 2005; 436: 946-52). This data is thus unlikely to reflect the role played by IFN-gamma in natural control of infection in individuals that resolve infection. This study will address this issue by carefully defining the kinetic of viral replication and the immune response when the biological effects of IFN-gamma are blocked. In order to establish a baseline for comparison, chimpanzees that have previously resolved HCV infection will be reinfected with homologous virus and virological and immunological parameters monitored. These animals should rapidly control and resolve infection (Shoukry et al. J Exp. Med. 2003; 197:1645-1655; Grakoui et al Science. 2003; 302: 659-662). Following this, study animals will be reinfected while the biological effects of IFN-gamma are simultaneously neutralized, and the kinetics of viral replication and the immune response again assessed. Comparison of these two infections will allow assessment of the role played by this cytokine in control of HCV replication. Neutralization of the effects of IFN-gamma is achieved by administration of a humanized monoclonal antibody against IFN-gamma that has been previously used in primates. Through this experiment we hope to define whether control of viral replication is dependent upon IFN-gamma. This will provide important information for development of preventive HCV vaccines and possibly therapies for repairing defects in the immune response that lead to chronic infection. There are few clues to the mechanisms by which clearance of HCV is achieved, and hence the factors governing the outcome of HCV infection (i.e. persistent, life-long replication of the virus versus acute resolution a few weeks after exposure to the virus) remain unknown. An understanding of the role played by the major anti-viral cytokine IFN-gamma will be critical for the design of vaccines to blunt replication of HCV in the liver and hopefully eliminate it before permanent damage to the organ can occur. This is critically important, as the choice of vaccine technologies to prime antiviral responses may make the difference between success and failure of immunization.