Program Director/PI (Last, First, Middle): Shaw, George M. Natural infection by HCV elicits immune responses that in a subset of humans lead to virus containment and elimination. These immune responses may in turn result in enhanced control of subsequent HCV infections. In other subjects, immune responses fail to contain the primary infection leading to viral persistence and disease. Distinguishing the particular immunological features of these different clinical outcomes may provide novel insights into correlates of immune protection and guide rational vaccine design. Projects 1 and 2 of this program project focus on B and T cell responses to the primary infecting virus strain(s) and explore how these immune responses affect the course of subsequent infections. Critical to the success of these studies is an unambiguous molecular identification of HCV strains responsible for acute primary infection and any subsequent infections. Also critical to the success of Projects 1 and 2 is a precise genetic and phenotypic mapping of B cell (neutralizing antibody, nAb) and T cell epitopes on infecting virus strains. Project 3, working in close coordination with Projects 1 and 2, will address these key issues. The specific hypothesis that Project 3 will test is as follows: Single genome sequencing (SGS) of plasma viral RNA (vRNA) will identify and distinguish virus strains responsible for acute primary HCV infection and reinfection and will provide a sensitive and dynamic indicator of host adaptive immune pressures targeting relevant B and T cell viral epitopes. To test this hypothesis, Project 3 will pursue three specific aims:
Aim #1 : To use single genome sequencing of plasma viral RNA to identify transmitted/founder (T/F) strains of HCV responsible for acute primary infection and reinfection.
Aim #2 : To determine the dynamics of elimination, replacement, or persistence of transmitted HCV strains in acute and chronic infection and to identify evolutionary pathways and population bottlenecks in the evolving viral quasispecies leading to persistence.
Aim #3 : To identify sites of immune recognition and selection across the complete HCV envelope (E1E2) gene and viral genome (core through NS5B) targeted by adaptive B and T cell responses. By providing an unambiguous molecular identification of HCV genomes responsible for acute primary infection, and by distinguishing these T/F genomes and their progeny from reinfecting virus strains, Project 3 will enable a precise mapping of B-cell and T-cell epitopes recognized by host immune responses and will facilitate an analysis of immune correlates of protection.
|Kinchen, Valerie J; Bailey, Justin R (2018) Defining Breadth of Hepatitis C Virus Neutralization. Front Immunol 9:1703|
|Rose, Rebecca; Lamers, Susanna L; Massaccesi, Guido et al. (2018) Complex patterns of Hepatitis-C virus longitudinal clustering in a high-risk population. Infect Genet Evol 58:77-82|
|Ke, Ruian; Li, Hui; Wang, Shuyi et al. (2018) Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence. Proc Natl Acad Sci U S A 115:E7139-E7148|
|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|
|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|
|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|
Showing the most recent 10 out of 59 publications