Recent studies have been encouraging that viral control of hepatitis C virus infection is possible. Prophylactic vaccines or efficient immunotherapies are urgently needed to reduce the disease burden of this global epidemic. HCV infects estimated 170 million people worldwide, and causes significant morbidity in developed and developing countries. Our knowledge about the mechanisms of control of viral replication and the failure to control HCV infection is still rather limited. Clearly, the outcome is determined in the early phase of the disease, therefore it seems paramount to study the earliest events that set the stage for clearance versus persistence of the virus. Various studies report an important role for both CD4+ and CD8+ in the control of viral replication. However, the majority of studies in human HCV infection utilized techniques that do not allow comprehensive and detailed assessment of the cellular immune response and were restricted to small numbers of subjects with acute infection. We propose here the analysis of the CD8+ T cell immunity in a large cohort of subjects with acute HCV infection and different transmission routes with the most precise and comprehensive techniques currently available. These studies include the analysis of the full breadth and magnitude of the CDS response on the single epitope level over the course of infection in subjects with different disease outcome, dissection of the functional and phenotypical properties of the detected specificities by the use of MHC class I tetramers and the detection of regions under selection pressure by longitudinal evolutionary data. Moreover, by utilizing an assay that allows for endogenous processing and presentation of autologous viral antigens we will be able to compare in a more physiological approach the CDS responses against the prototype HCV sequence (H77) with the response against the autologous virus. In concert with studies that address how the virus evades the activated host immune system and how they interact with the individual's CD4+ T-cell immunity this will provide important insights into the mechanisms that contribute to control and persistence of viral infection. Dissection of these mechanisms will be an important contribution to develop prophylactic vaccines or immunotherapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI066345-04
Application #
7676722
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$252,359
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Yu, Wen-Han; Cosgrove, Cormac; Berger, Christoph T et al. (2018) ADCC-Mediated CD56DIM NK Cell Responses Are Associated with Early HBsAg Clearance in Acute HBV Infection. Pathog Immun 3:2-18
Forconi, Catherine S; Cosgrove, Cormac P; Saikumar-Lakshmi, Pryia et al. (2018) Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas. Blood Adv 2:1101-1114
Torres-Cornejo, Almudena; Lauer, Georg M (2017) Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines. Pathog Immun 2:102-125
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
Wolski, David; Foote, Peter K; Chen, Diana Y et al. (2017) Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection. Immunity 47:648-663.e8
Rodrigo, Chaturaka; Walker, Melanie R; Leung, Preston et al. (2017) Limited naturally occurring escape in broadly neutralizing antibody epitopes in hepatitis C glycoprotein E2 and constrained sequence usage in acute infection. Infect Genet Evol 49:88-96
Rodrigo, C; Eltahla, A A; Bull, R A et al. (2017) Phylogenetic analysis of full-length, early infection, hepatitis C virus genomes among people with intravenous drug use: the InC3 Study. J Viral Hepat 24:43-52
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
Page, Kimberly; Mirzazadeh, Ali; Rice, Thomas M et al. (2016) Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative. Open Forum Infect Dis 3:ofw024
Gunn, Bronwyn; Schneider, Jeffrey; Shansab, Maryam et al. (2016) Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16. Mucosal Immunol 9:1549-1558

Showing the most recent 10 out of 57 publications