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)
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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