HCV has evolved remarkable mechanisms to ensure its persistence as a chronic infection. The mechanisms underlying the host innate and adaptive immune response to HCV infection, as well as the means by which HCV circumvents these measures to establish persistent infection, are not well characterized. Progress in understanding these mechanisms has been slowed by impediments in tissue culture and limitations in the ability to use authentic differentiated hepatocytes. However, recent advances in functional genomics and primary hepatocyte tissue culture methodologies now make identification of authentic host genes that contain HCV replication an attainable possibility. We hypothesize that the hepatocyte is a key locus for host control and containment of HCV infection. We propose the following Aims: 1. Define antiviral type IIFNstimulated genes in the hepatocyte and characterize their role in the establishment of chronicity. 2. Define the effects of HCV infection on the interaction of hepatocytes with the cellular immune response. 3. Define antiviral type II IFN-stimulated genes in the hepatocyte that participate in the noncytolytic clearance of HCV infection and characterize their role in the establishment of chronicity. To accomplish these Aims, we will utilize a high throughput whole genome siRNA screen we have successfully developed to identify genes that participate in HCV replication. We will use this screen to identify genes that participate in IFN-a and IFN-y's noncytolytic antiviral effects. We will exploit recent major advances in our ability to sustain primary human hepatocytes that both maintain function and support HCV infection. Primary hepatocytes from patient groups with variable susceptibility to chronic HCV will be studied for alterations in key antiviral IFN-stimulated genes identified in our functional genomic screens. The studies in this proposal are focused and thematically organized around the key role of the hepatocyte in the innate and adaptive immune responses, and their failure in chronic HCV. They have great potential to identify novel means of interrupting the viral lifecycle and preventing persistence of this model chronic infection.

Public Health Relevance

HCV, which infects over 170 million persons, has a remarkable predilection for chronicity. The basis for HCV's chronicity and its recalcitrance to innate and adaptive immune control is not well understood. We will take important steps to identify the hepatocyte-based antiviral functions that represent the targets of HCV's unique strategies for persistence and in so doing identify novel strategies for preventing the chronicity of this important Emerging Pathogen

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082630-04
Application #
8376113
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
2012-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$350,994
Indirect Cost
$95,229
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Bengsch, Bertram; Ohtani, Takuya; Herati, Ramin Sedaghat et al. (2017) Deep immune profiling by mass cytometry links human T and NK cell differentiation and cytotoxic molecule expression patterns. J Immunol Methods :
Herati, Ramin Sedaghat; Muselman, Alexander; Vella, Laura et al. (2017) Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells. Sci Immunol 2:
Stelma, Femke; van der Ree, Meike H; Sinnige, Marjan J et al. (2017) Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101. Hepatology 66:57-68
Huang, Alexander C; Postow, Michael A; Orlowski, Robert J et al. (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65
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
Chen, Zeyu; Stelekati, Erietta; Kurachi, Makoto et al. (2017) miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb. Cell Rep 20:2584-2597
Hedegaard, Ditte L; Tully, Damien C; Rowe, Ian A et al. (2017) High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease. J Hepatol 66:28-38
Sise, Meghan E; Backman, Elke; Ortiz, Guillermo A et al. (2017) Effect of Sofosbuvir-Based Hepatitis C Virus Therapy on Kidney Function in Patients with CKD. Clin J Am Soc Nephrol 12:1615-1623
Kurioka, Ayako; Jahun, Aminu S; Hannaway, Rachel F et al. (2017) Shared and Distinct Phenotypes and Functions of Human CD161++ V?7.2+ T Cell Subsets. Front Immunol 8:1031
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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