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Walker, ChristopherEducation
Research Interests Dr. Walker's research focuses primarily on the immunology and pathogenesis of Hepatitis C virus (HCV) infection in humans and chimpanzees, the only animal model for HCV. HCV infects about 200 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma. Our laboratory is interested in the role of the immune system in governing the outcome of infection. We have demonstrated that clearance of the virus in chimpanzees is temporally associated with a robust immune response in the liver. CD8+ T lymphocytes that recognize and then kill HCV-infected hepatocytes are particularly important for protection from chronic infection. Most recently we have determined that these HCV-specific T cells are very long-lived in animals that recovered from infection. Importantly, these memory immune cells react rapidly upon re-exposure to HCV. We have also characterized immune responses in animals with persistent viremia. Surprisingly, HCV-specific CD8+ T cells were also present in their livers despite years of virus replication. However, the epitopes targeted by these CD8+ T cells are usually mutated in virus populations that circulated in the animals. Escape mutations in the epitopes prevented class I MHC binding or T cell recognition and usually arose in the first few months of infection. Mutations remained fixed in the viral quasispecies for years. Statistical analysis of the pattern of mutation in the epitopes strongly supported the hypothesis that they resulted from immune selection pressure and not chance.New research initiatives in our laboratory include vaccine development for HCV using the adeno-associated virus (AAV) vector platform established at CRI by Dr. P. Johnson and colleagues. Drs. Walker and Johnson are already co-investigators on a HIVRAD program project grant for development of SIV/HIV vaccines. Other collaborative research projects include (1) development of a murine model for expression of HCV protein in the liver using recombinant AAV vectors with Dr. Sferra at CRI funded by an SBIR grant with Epimmune Corporation and (2) investigation of the host-pathogen relationship in mice infected with the respiratory syncytial virus with Dr. Durbin., HCV infects about 200 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma. Most of these individuals (approximately 70%) fail to clear the virus and are infected for life, while the remainder spontaneously resolve the infection a few weeks after exposure to HCV. Our laboratory studies how the immune system governs the outcome of HCV infection. Cellular immune responses that lead to destruction of virus-infected liver cells (hepatocytes) are particularly important for resolution of infection. Key components of this successful cellular immune response are helper (CD4+) and killer (CD8+) T lymphocytes that co-operate to eliminate HCV-infected hepatocytes. Individuals that spontaneously recover from HCV infection also have very long-lived memory T cells that can react rapidly upon re-exposure to the virus and accelerate its clearance from the body. This naturally acquired protective immunity suggests that a vaccine to prevent HCV persistence is an achievable goal. We also study why cellular immune responses fail in individuals who develop chronic hepatitis C. The virus does undermine helper T cell responses, although we do not yet understand how this happens. Killer T cell responses are also inadequate, at least in part because HCV mutates so that infected cells are invisible. We are now investigating other mechanisms used by HCV to silence T cells, including manipulation of the body's molecular switches (for instance PD-1 and CTLA-4) that turn immunity on and off. A second research initiative is to develop vaccines that can reproduce the natural protective immunity induced by resolution of HCV infection. Immunization with recombinant adeno-associated virus (AAV) vectors carrying HCV genes may be one way to mimic this natural immunity. We are now characterizing the immune responses elicited by these AAV vectors in animals. Our goal is to translate this research into a vaccine that tips the human immune system away from failure leading to HCV persistence and towards successful resolution of infection. Selected Publications Bowen D and Walker CM. Mutational escape from CD8+ cell immunity: HCV evolution, from chimpanzees to man. J Exp Med 201:1709-1714, 2005. (Commentary Review) Bowen D and Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436:946-952, 2005. Kimura Y, Gushima T, Rawale S, Kaumaya P, and Walker CM. 2005. Escape mutations alter proteasome processing of major histocompatibility complex class I-restricted epitopes in persistent hepatitis C virus infection. J Virol 79(8):4870-4876. Meyer-Olson D, Shoukry NH, Brady KW, Kim H, Olson DP, Hartman K, Shintani AK, Walker CM, Kalams SA. 2004. Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape. J. Exp. Med. 200:307-319. Shoukry NH, Sidney J, Sette A, and Walker CM. 2004. Conserved hierarchy of helper T cell responses in a chimpanzee during primary and secondary hepatitis C virus infections. J Immunol 172:483-492. Shoukry NH, Cawthon AG and Walker CM. 2004. Cell-mediated immunity and the outcome of hepatitis C virus infection. Ann. Rev. Microbiol. 50:391-424. Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA, and Walker CM. 2003. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 197:1645-1655. Grakoui A, Shoukry NH, Woollard D, Han J-H, Hanson HL, Ghrayeb J, Murthy KK, Rice CM, and Walker CM. 2003. HCV persistence and immune evasion in the absence of memory T cell help. Science 302:659-662. Erickson, A.L., Kimura, Y., Igarashi, S., Eichelberger, J., Houghton, M., Sidney, J., McKinney, D., Sette, A., Hughes, A.L., and Walker, C.M. 2001. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15:883-895. Contact Christopher Walker, PhD Director, Center for Vaccines and Immunity Columbus Children's Research Institute Room WA4011, 700 Childrens Drive Columbus, OH 43205 p: 614.722.2735 | f: 614.722.3680 |
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