HCV infection of humans induces a complex immune response characterized by induction of innate immunity followed by both cell mediated and humoral adaptive immune responses. In -20% of acute HCV Infections, the anti-HCV Immune response controls the infection. Analysis of both human and primate HCV infection indicates that clearance is associated with robust CD4 and CDS T cell responses specific for HCV epitopes. Although the generation of neutralizing humoral responses is also likely important in HCV infection, their ultimate role in clearance remains to be determined. Understanding the mechanisms of immune evasion that allow HCV to develop and maintain chronic infection in the majority of cases is critical to prophylactic and therapeutic vaccine development. HCV has a highly error-prone polymerase with a correspondingly high mutation rate, allowing HCV to rapidly escape developing immune responses. Therefore, complete understanding of the successful immune response to HCV with its mechanisms of evasion and escape from sterilizing immunity requires serial analysis of both HCV sequence and HCV-specific adaptive immune responses from the time of initial infection until outcome is determined. In addition to the technical complexity of specific quantitative analysis of epitope specific T cell and humoral responses, the study of HCV immunity is further complicated by the fact that acute infection is generally asymptomatic and therefore typically not detected. The vast majority of HCV infected patients are therefore diagnosed during their chronic phase, long after the critical immune responses to acute infection are generated. The Center includes a unique cohort of injection drug users followed on a monthly basis, thereby allowing high frequency detection of de novo acute HCV infection and longitudinal evaluation of infection outcome. Thus, the proposed research brings together unique patient resources with leaders in the study of HCV-specific T cell and humoral immune responses and HCV sequence evolution. The combination of cohort and sequence evolution and immunologic expertise make the proposed projects feasible, potentially increasing understanding of human chronic viral infections and enhancing development of immunotherapies.

Public Health Relevance

Infection with hepatitis C virus (HCV) is the number one reason for people to need liver transplantation in the United States, but the early infection is hard to detect. We study people at high risk for HCV infection, and focus on the early immune responses to HCV. Understanding how the virus escapes immune responses that eliminate most viral infections could guide future efforts to detect, treat, and prevent HCV infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BP-M (J1))
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Koshy, Rajen
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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von Delft, Annette; Humphreys, Isla S; Brown, Anthony et al. (2016) The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design. Gut 65:112-23
Patel, Eshan U; Cox, Andrea L; Mehta, Shruti H et al. (2016) Use of Hepatitis C Virus (HCV) Immunoglobulin G Antibody Avidity as a Biomarker to Estimate the Population-Level Incidence of HCV Infection. J Infect Dis 214:344-52
Vergara, Candelaria; Thio, Chloe L; Thomas, David et al. (2016) Polymorphisms in melanoma differentiation-associated gene 5 are not associated with clearance of hepatitis C virus in a European American population. Hepatology 63:1061-2
Wasilewski, Lisa N; Ray, Stuart C; Bailey, Justin R (2016) Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles. J Gen Virol 97:2883-2893
Rodrigo, Chaturaka; Eltahla, Auda A; Bull, Rowena A et al. (2016) Historical Trends in the Hepatitis C Virus Epidemics in North America and Australia. J Infect Dis 214:1383-1389
Wasilewski, Lisa N; El-Diwany, Ramy; Munshaw, Supriya et al. (2016) A Hepatitis C Virus Envelope Polymorphism Confers Resistance to Neutralization by Polyclonal Sera and Broadly Neutralizing Monoclonal Antibodies. J Virol 90:3773-82
Hajarizadeh, Behzad; Grady, Bart; Page, Kimberly et al. (2015) Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study. PLoS One 10:e0122232
Hajarizadeh, B; Grady, B; Page, K et al. (2015) Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study. J Viral Hepat 22:708-17
Bailey, Justin R; Dowd, Kimberly A; Snider, Anna E et al. (2015) CD4+ T-Cell-Dependent Reduction in Hepatitis C Virus-Specific Neutralizing Antibody Responses After Coinfection With Human Immunodeficiency Virus. J Infect Dis 212:914-23
El-Diwany, Ramy; Wasilewski, Lisa N; Witwer, Kenneth W et al. (2015) Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release. J Virol 89:9454-64

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