Christopher M. Walker, Ph.D.
Department of Pediatrics
Director, Center for Vaccines and Immunity
Wilby S. Cowan Endowed Chair in Pediatric Research
The Research Institute at Nationwide Children's Hospital
The College of Medicine and Public Health
The Ohio State University
Columbus Children’s Research Institute
700 Children’s Drive
Columbus, OH 43205
Department of Molecular Virology, Immunology, and Medical Genetics
A major focus of our research is to understand how immune responses are subverted in a serious persistent virus infection of humans so that new vaccines can be developed. At the same time we are attempting to improve the success gene replacement for diseases like muscular dystrophy by preventing immunity to therapeutic proteins that might be recognized as foreign. The opposing goals of restoring immunity in one situation (persistent virus infection) and silencing it in another (gene therapy) are linked by our interest in common molecular switches that turn the human immune system on or off.
Turning immunity on: the challenge of hepatitis C virus infection. The hepatitis C virus (HCV) can establish a persistent life-long infection in humans with potentially serious consequences including cirrhosis and hepatocellular carcinoma. Approximately 200 million people are infected with HCV globally but there is no preventative vaccine and current therapies are expensive, toxic, and often fail to eradicate the virus. Our goal is to understand why T lymphocytes, a type of white blood cell critical for control of virus infection, fail to eliminate infected hepatocytes that produce about 1 trillion new HCV particles each day in individuals with chronic hepatitis C. Studies in our laboratory funded by the National Institutes of Health and the Bill and Melinda Gates Foundation suggest that multiple defects in T cell immunity contribute to HCV persistence. We are unraveling these pathways in HCV-infected adults, and also infants who acquire the virus from their mothers, to design vaccine strategies for successful prevention and treatment of chronic hepatitis C.
Turning immunity off: towards successful gene therapy. Clearing the hurdle of host immunity will be critical for durable gene therapy of catastrophic diseases like muscular dystrophy. Modified adeno-associated virus (AAV) vectors are now being used to deliver corrected copies of genes to humans with serious inherited diseases like muscular dystrophy and hemophilia. Therapeutic proteins encoded by these replacement genes could be recognized as foreign by the human immune system. We are currently studying whether T lymphocytes limit the success of gene therapy by eliminating AAV vector-treated cells that produce the therapeutic proteins. This effort is focused on children with muscular dystrophy who are treated with AAV vectors carrying corrected copies of dystrophin or related proteins. Our practical goal is to develop approaches for silencing immunity to helpful therapeutic proteins like dystrophin.
Paliard X, Liu Y, Wagner R, Wolf H, Baenzinger J and Walker CM. Priming of strong broad and long-lived HIV-1p55gag-specific CTL following administration of a virus-like particle vaccine in rhesus macaques. AIDS Res Hum Retroviruses, 16(3): 273-282, 2000.
Sidney J, Dzuris JL, Newman MJ, Johnson RP, Amitinder K, Walker CM, Appella E, Mothe B, Watkins DI, Sette A. Definition of the mamu A*01 peptide binding specificity: application to the identification of wild-type and optimized ligands from simian immunodeficiency virus regulatory. J Immunol 165:6387-6399, 2000.
McKinney DM, Erickson AL, Walker CM, Thimme R, Chisari FV, Sidney J and Sette A. Identification of five different patr class I molecules that bind HLA supertype peptides and definition of their peptide binding motifs. J Immunol 165:4414-4422, 2000.
Paliard X, Doe B, Selby MJ, Hartog K, Lee AY, Burke R-L, and Walker CM. Induction of Herpes Simplex Virus (HSV) gB-specific cytotoxic T lymphocytes in TAP1-deficient mice by genetic immunization but not HSV infection. Virology 282:56-64, 2001.
Buck CB, Shen X, Egan MA, Pierson TC, Walker CM, Siliciano RF. The human immunodeficiency virus type 1 gag gene encodes an internal ribosome entry site. J Virol 75:181-191, 2001.
Erickson AL, Kimura Y, Igarashi S, Eichelberger J, Houghton M, Sidney J, McKinney D, Sette A, Hughes AL, and Walker CM. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15:883-895, 2001.
Davis NL, West A, Reap E, MacDonald G, Collier M, Dryga S, Maughan M, Connell M, Walker CM, McGrath K, Cecil C, Ping L-H, Frelinger J, Olmsted R, Keith P, Swanstrom R, Williamson C, Johnson P, Montefiori D, and Johnston RE. Alphavirus replicon particles as candidate HIV vaccines. JUBMB Life 53:209-211, 2002.
Meyer-Olson D, Brady KW, Blackard JT, Allen TM, Islam S, Shoukry NH, Hartman K, Walker CM, and Kalams SA. Analysis of the TCRb variable gene repertoire in chimpanzees: identification of functional monologs to human pseudogenes. J Immunol 170:4161-4169, 2003.
Sette A, Sidney J, Livingston BD, Dzuris JL, Crimi C, Walker CM, Southwood S, Collins EJ, Hughes AL. Class I molecules with similar peptide-binding specificities are the result of both common ancestry and convergent evolution. Immunogenetics 54:830-41, 2003.
Shoukry NH, Grakoui A, Houghton M, Chien DY, Ghrayeb J, Reimann KA, and Walker CM. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 197:1645-1655, 2003.
Sundaram R, Sun Y, Walker CM, Lemonnier FA, Jacobson S, and Kaumaya PTP. A novel multivalent human CTL peptide construct elicits robust cellular immune responses in HLA-A*0201 transgenic mice: implications for HTLV-1 vaccine design. Vaccine 21:2767-2781, 2003.
Woollard DJ, Shoukry NH, Murthy KK, Campbell KJ, Grakoui R and Walker CM. Characterization of HCV-specific Patr class II restricted CD4+ T-cell responses in an acutely infected chimpanzee. Hepatology 38:1297-1306, 2003.
Grakoui A, Shoukry NH, Woollard D, Han J-H, Hanson HL, Ghrayeb J, Murthy KK, Rice CM, and Walker CM. HCV persistence and immune evasion in the absence of memory T cell help. Science 302:659-662, 2003.
Shoukry NH, Sidney J, Sette A, and Walker CM. Conserved hierarchy of helper T cell responses in a chimpanzee during primary and secondary hepatitis C virus infections. J Immunol 172:483-492, 2004.
Larsson M, Babcock E, Grakoui A, Shoukry NH, Rice C, Walker CM and Bhardwaj N. Lack of phenotypic and functional impairment in dendritic cells from chimpanzees chronically infected with hepatitis C virus. J. Virol. 78:6151-6161, 2004.
Meyer-Olson D, Shoukry NH, Brady KW, Kim H, Olson DP, Hartman K, Shintani AK, Walker CM, Kalams SA. Limited T cell receptor diversity of HCV-specific T cell responses is associated with CTL escape. J. Exp. Med. 200:307-319, 2004.
Elkington R.,Shoukry NH, Walker S, Crough, T, Fazou, C, Kaur T, Walker CM and Khanna R. Cross-reactive recognition of human and primate cytomegalovirus sequences by human CD4 cytotoxic T lymphocytes specific for glycoprotein B and H. Eur. J. Immunol. 34(11):3216-3226, 2004.
Sundaram R, Lynch M, Rawale S, Dakappagari N, Young D, Walker CM, Lemmonier F, Jacobson S, and Kaumaya PTB. Protective efficacy of multiepitope human leukocyte antigen-A*0201 restricted cytotoxic T lymphocyte peptide construct against challenge with human T-cell lymphotropic virus type 1 TAX recombinant vaccinia virus. J. Acquir. Immune Defic. Syndr. 37(3):1329-1339, 2004.
Kimura Y, Gushima T, Rawale S, Kaumaya P, and Walker CM. 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, 2005.
Bowen D and Walker CM. Mutational escape from CD8+ cell immunity: HCV evolution, from chimpanzees to man. J Exp Med 201:1709-1714, 2005.
Bowen D and Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436:946-952, 2005.