The primary objective of Project 2 is to expand on our studies of humoral immune response to acute hepatitis C virus (HCV) infection by examining the clinical and molecular correlates of potent neutralizing antibody responses. We have recently demonstrated that anti-HCV neutralizing antibodies drive the evolution of HCV proteins El and E2 during acute infection, indicating that neutralizing antibodies detected in an in vitro assay are capable of reducing viral fitness in vivo. In addition, available evidence from acute Infections indicates that high-titer neutralizing antibody responses are present in persons who go on to clear viremia, and not in those who progress to chronicity. We h3T30thesize that neutralizing antibodies are a predictive marker of clearance of acute HCV infection, and that evasion of these responses is a constrained mechanism for viral persistence. Thus, we propose the following aims to elucidate the clinical utility and basic mechanisms of HCV neutralization: (I) To define the positive predictive value of a potent anti-HCV neutralizing antibody response as a predictor of clearance during acute infection, and (II) To investigate the mechanisms by which HCV evades neutralizing antibody responses during acute infection. Results of studies of cellular immune responses from Project 1 will be integrated to expand knowledge of the interplay between humoral and cellular immune responses to HCV in humans. We have already demonstrated that we can obtain the critical specimens required for this investigation and will be able to conduct unique longitudinal studies of adaptive immune responses in persons transitioning from acute to established infection.

Public Health Relevance

Project 2 is focused on antibody responses to hepatifis C virus (HCV) that block HCV infecfion of liverderived cells. We will determine whether these neutralizing antibody responses occur earlier in people who resolve their infection without needing treatment, and in those people who become chronically infected we will study how the virus mutates to avoid neutralization.

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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Johns Hopkins University
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Kinchen, Valerie J; Cox, Andrea L; Bailey, Justin R (2018) Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine? Trends Microbiol 26:854-864
Esmaeili, Aryan; Mirzazadeh, Ali; Morris, Meghan D et al. (2018) The Effect of Female Sex on Hepatitis C Incidence Among People Who Inject Drugs: Results From the International Multicohort InC3 Collaborative. Clin Infect Dis 66:20-28
Kinchen, Valerie J; Zahid, Muhammad N; Flyak, Andrew I et al. (2018) Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection. Cell Host Microbe 24:717-730.e5
Kinchen, Valerie J; Bailey, Justin R (2018) Defining Breadth of Hepatitis C Virus Neutralization. Front Immunol 9:1703
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Bailey, Justin R; Barnes, Eleanor; Cox, Andrea L (2018) Approaches, Progress, and Challenges to Hepatitis C Vaccine Development. Gastroenterology :
Mankowski, Madeleine C; Kinchen, Valerie J; Wasilewski, Lisa N et al. (2018) Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms. Proc Natl Acad Sci U S A 115:E82-E91
Morris, Meghan D; Shiboski, Stephen; Bruneau, Julie et al. (2017) Geographic Differences in Temporal Incidence Trends of Hepatitis C Virus Infection Among People Who Inject Drugs: The InC3 Collaboration. Clin Infect Dis 64:860-869
Vergara, C; Thio, C; Latanich, R et al. (2017) Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections. Genes Immun 18:82-87

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