Liver disease continues to be a predominant etiology of death among HIV-infected persons in countries where HAART is available. 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, which is currently undergoing clinical trials for treatment of HIV.
In Specific Aim 1 we will characterize the effect of CCR5 on in vivo hepatic fibrogenesis.
Specific Aim 2 will examine the immune regulatory mechanisms which may affect fibrosis development in relation to CCR5 mutation or blockade, and Specific Aim 3 will utilize in vivo methods to characterize the effect of CCR5 on HCV and the cytokine environment. We hypothesize that either host mutation in CCR5 or pharmacologic blockade will reduce hepatic fibrosis and will attempt to elucidate the mechanism(s) by which this occurs.

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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AIDS Clinical Studies and Epidemiology Study Section (ACE)
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Brobst, Susan W
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University of Cincinnati
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
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
Dahari, Harel; Guedj, Jeremie; Perelson, Alan S (2011) Silibinin mode of action against hepatitis C virus: a controversy yet to be resolved. Hepatology 54:749
Guedj, Jeremie; Perelson, Alan S (2011) Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: implications for treatment duration. Hepatology 53:1801-8
Rong, Libin; Dahari, Harel; Ribeiro, Ruy M et al. (2010) Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2:30ra32

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