Chronic hepatitis C virus (HCV) infection develops in 70-80% of all exposed individuals and affects 3% of the world's population. There is a need for more effective and better-tolerated HCV therapies. Our long-term goals are to define host-HCV molecular interactions and in so doing, to identify novel therapeutic agents for HCV therapy. We have completed a functional genomic screen for host cofactors for HCV replication using a whole- genome siRNA library. Among the many novel host cofactors identified is PI4KA, a phosphatidylinositol 4- kinase (PI 4-kinase). We hypothesize that PI4KA is necessary for formation of the altered host membranes required for HCV replication. This proposal describes a 5 year mentored training program to acquire further technical skills in the fields of molecular virology, phosphoinositides and cell trafficking, and cell imaging. These skills will be used to develop novel model systems to study the formation and composition of the HCV replication complex and its associated host membranes and proteins.
The specific aims of this project are (1) to characterize the specificity of PI4KA inhibition for suppression of HCV replication, (2) to characterize the role of PI4KA through the viral replication cycle, and (3) to develop systems to study HCV replication complex assembly and composition. Although the specific aims are directed towards PI4KA, the systems and techniques to be developed during the award period will be applied to the study of other host cofactors of HCV replication. The proposed research will have direct public health benefits as a better understanding of the mechanisms that underline HCV replication complex assembly may lead to novel targets for HCV therapies. A better understanding of the HCV-host relationship is a stated goal of the NIH Action Plan for Liver Disease Research (Goal B2a). We have recently performed a whole-genome screen for human (host) proteins that are required by the hepatitis C virus for its replication. Such proteins are potential targets for new therapies for HCV. This proposal describes a 5-year research plan focusing on developing new systems to study how host cofactors direct the assembly of HCV replication complexes.

Public Health Relevance

We have recently performed a whole-genome screen for human (host) proteins that are required by the hepatitis C virus for its replication. Such proteins are potential targets for new therapies for HCV. This proposal describes a 5-year research plan focusing on developing new systems to study how host cofactors direct the assembly of HCV replication complexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI083785-03
Application #
8296579
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Koshy, Rajen
Project Start
2010-06-15
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$132,300
Indirect Cost
$9,800
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Salloum, Shadi; Wang, Hongliang; Ferguson, Charles et al. (2013) Rab18 binds to hepatitis C virus NS5A and promotes interaction between sites of viral replication and lipid droplets. PLoS Pathog 9:e1003513
Huang, Yuehua; Tai, Andrew W; Tong, Shuping et al. (2013) HBV core promoter mutations promote cellular proliferation through E2F1-mediated upregulation of S-phase kinase-associated protein 2 transcription. J Hepatol 58:1068-73
Zhao, Hong; Lin, Wenyu; Kumthip, Kattareeya et al. (2012) A functional genomic screen reveals novel host genes that mediate interferon-alpha's effects against hepatitis C virus. J Hepatol 56:326-33
Huang, Yuehua; Tong, Shuping; Tai, Andrew W et al. (2011) Hepatitis B virus core promoter mutations contribute to hepatocarcinogenesis by deregulating SKP2 and its target, p21. Gastroenterology 141:1412-21, 1421.e1-5
Tai, Andrew W; Salloum, Shadi (2011) The role of the phosphatidylinositol 4-kinase PI4KA in hepatitis C virus-induced host membrane rearrangement. PLoS One 6:e26300
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