Abstract

The causes of liver disease are complex and include chronic viral hepatitis (B,C,D), alcohol, drug-associated hepatotoxicities and metabolic disorders. However, fibrosis leading to cirrhosis and end-stage liver disease is the common pathway for hepatic injury. Rates of fibrotic progression are highly variable, and reflect differences in host response to disease. One host factor, a chemokine receptor named CCR5 may play a central role in modulating hepatic fibrosis, and will be the primary subject of exploration in this study. We will examine the effects of CCR5 deletion mutations (CCR5- ?32) in a large and well- characterized cohort of patients with hemophilia who were followed for up to 18 years in the NIH Multicenter Hemophilia Cohort Studies (MHCS). In addition we will utilize samples derived from a study of HIV-infected patients treated with a unique CCR5/CCR2 inhibitor, Cenicriviroc.
In Specific Aim 1 we will characterize the effect of CCR5 on in vivo hepatic fibrogenesis, focusing on both intrinsic (gene polymorphism) and extrinsic (CVC) associated CCR5 blockade.
Specific Aim 2 will examine the immune regulatory mechanisms which may affect fibrosis development in relation to CCR5 mutation or blockade using both lymphocytes and liver tissue.
Specific Aim 3 will utilize in vivo methods to characterize the effec of CCR5 antagonism on HCV and the immune environment. Using RNAseq and other experimental methods we will determine the pathway(s) involved with modulation of HCV replication and hepatic fibrogenesis. We hypothesize that either host mutation in CCR5 coding genes or pharmacologic blockade will reduce hepatic fibrosis and will attempt to elucidate the mechanism(s) by which this occurs. This study may generate new paradigms for prevention of hepatic fibrosis in those with HIV infection.

Public Health Relevance

Patients with HIV are at risk for liver injury and scarring. Use of some types of antiviral drugs may slow disease progression. We will study the role of one class of drugs (CCR5 blockers) to alter liver scarring.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065256-08
Application #
9410480
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Chiou, Chen-Chia Christine C
Project Start
2006-04-15
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221

  Publications

Sherman, Kenneth E; Abdel-Hameed, Enass; Rouster, Susan D et al. (2018) Improvement in Hepatic Fibrosis Biomarkers Associated with Chemokine Receptor Inactivation through Mutation or Therapeutic Blockade. Clin Infect Dis :
Blackard, Jason T; Ma, Gang; Polen, Clarissa et al. (2016) Recombination among GB virus C (GBV-C) isolates in the United States. J Gen Virol 97:1537-44
Blackard, Jason T; Ma, Gang; Sengupta, Satarupa et al. (2014) Evidence of distinct populations of hepatitis C virus in the liver and plasma of patients co-infected with HIV and HCV. J Med Virol 86:1332-41
Sherman, Kenneth E; Guedj, Jeremie; Shata, Mohamed Tarek et al. (2014) Modulation of HCV replication after combination antiretroviral therapy in HCV/HIV co-infected patients. Sci Transl Med 6:246ra98
Dahari, Harel; Cotler, Scott J; Layden, Thomas J et al. (2013) Understanding triphasic HCV decline during treatment in the era of IL28B polymorphisms and direct acting antiviral agents via mathematical modeling. J Hepatol 58:840-2
Guedj, Jeremie; Dahari, Harel; Uprichard, Susan L et al. (2013) The hepatitis C virus NS5A inhibitor daclatasvir has a dual mode of action and leads to a new virus half-life estimate. Expert Rev Gastroenterol Hepatol 7:397-9
Chatterjee, Anushree; Guedj, Jeremie; Perelson, Alan S (2012) Mathematical modelling of HCV infection: what can it teach us in the era of direct-acting antiviral agents? Antivir Ther 17:1171-82
Guedj, Jeremie; Dahari, Harel; Pohl, Ralf T et al. (2012) Understanding silibinin's modes of action against HCV using viral kinetic modeling. J Hepatol 56:1019-24
Guedj, Jeremie; Dahari, Harel; Shudo, Emi et al. (2012) Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128). Hepatology 55:1030-7
Guedj, H; Guedj, J; Negro, F et al. (2012) The impact of fibrosis and steatosis on early viral kinetics in HCV genotype 1-infected patients treated with Peg-IFN-alfa-2a and ribavirin. J Viral Hepat 19:488-96

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