Our laboratory investigates the host immune response to viral infection, particularly hepatitis C virus (HCV), including the role of the immune response in clearance of HCV upon exposure to this virus. We study the humoral and cellular immune responses to HCV from the earliest phases of infection through years following infection, allowing assessment of the response irrespective of the outcome of infection. A significant barrier to the development of an HCV vaccine is that HCV is a highly diverse virus. Our laboratory is developing an HCV vaccine that may overcome this diversity and stimulate an effective immune response. Despite ongoing viremia with sequence evolution in those chronically infected with HCV, we have shown that in the majority of individuals, the CD8+ T cell responses generated early in HCV infection decline in peripheral blood and are not replaced with new responses. Our results suggest that the development of HCV-specific T cell clones is arrested during the first year of infection. We are currently investigating the molecular phenotypes associated with this loss of functional activity and are characterizing differences between the functional and molecular phenotype of lymphocytes recognizing epitopes that undergo substitution and those recognizing epitopes that do not. Identifying the molecules associated with decreased function might provide targets for blockade, enhancing immunogenicity of a vaccine. Thus, the overall goal of our program includes understanding immune system failure to clear HCV infection in order to overcome the mechanisms of immune evasion that limit HCV vaccine efficacy.

Netski D, Mosbruger T, Depla E, Maertens G, Ray S, Hamilton R, Roundtree S, Thomas D, McKeating J, Cox A. (2005) Humoral Immune Response in Acute HCV Infection. Clinical Infectious Diseases 79(8):5185-202 [PubMed]

Cox A, Mosbruger T, Lauer G, Pardoll D, Thomas D, Ray S. (2005) Comprehensive Analyses of CD8+ T cell Responses During Longitudinal Study of Acute Human Hepatitis C. Hepatology 80(10):4758-70. [PubMed]

Cox A, Mosbruger T, Mao Q, Liu Z, Wang X-H, Yang H-C, Sidney J, Sette A, Pardoll D, Thomas D, Ray R. (2005) Cellular Immune Selection with Hepatitis C Virus Persistence in Humans. J. Exp. Med. 203(5):1357-69 [PubMed]

Cox A, Netski D, Mosbruger T, Sherman S, Strathdee S, Ompad D, Vlahov D, Chien D, Shyamala V, Ray S, Thomas D. (2005) Prospective Evaluation of Community-Acquired Acute-Phase Hepatitis C Virus Infection. Clinical Infectious Diseases 80(13):6441-57 [PubMed]

Mehta S, Cox A, Hoover D, Wang X-H, Mao Q, Ray S, Strathdee S, Vlahov, D, Thomas D. (2002) Protection Against Hepatitis C Persistence. Lancet 5(6):533-8 [PubMed]