Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) are common viruses that afflict millions of Americans. Infection with HCV causes progressive liver fibrosis, which frequently results in end-stage liver disease and hepatocellular carcinoma. The course of HCV is worsened by co-infection with HIV. The mechanism by which HIV exacerbates HCV liver disease is still not known. We demonstrate that 1) livers from HCV mono-infected patients have elevated expression of TRAIL (TNF- related apoptosis inducing ligand) and 2) HIV envelope gp120 binding to the chemokine receptor CXCR4 induces a G-protein independent, JNK dependent, TRAIL-R2 upregulation and acquired sensitivity to TRAIL-induced death. These observations allow us to propose the following model of HCV/HIV co-infection that is responsible for enhanced liver disease in co-infected people: (i) HCV infection enhances TRAIL expression in hepatocytes, (ii) HIV infection increases TRAIL-R2 expression and confers TRAIL sensitivity in hepatocytes, and that (iii) HCV and HIV co-infection consequently results in TRAIL-dependent hepatotoxicity. The current proposal will evaluate this conceptual model to explain the enhanced liver disease progression in HCV/HIV co-infected people through the following hypothesis-driven specific aims. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK077575-01
Application #
7228784
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Doo, Edward
Project Start
2007-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
1
Fiscal Year
2007
Total Cost
$222,000
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Rizza, Stacey A; Challagundla, Kishore B; Natesampillai, Sekar et al. (2011) TRAIL dependent fratricidal killing of gp120 primed hepatocytes by HCV core expressing hepatocytes. PLoS One 6:e27171
Singh, Vijay P; Bren, Gary D; Algeciras-Schimnich, Alicia et al. (2009) Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis. Am J Physiol Gastrointest Liver Physiol 296:G1040-6
Babu, Challagundla K; Suwansrinon, Kanitta; Bren, Gary D et al. (2009) HIV induces TRAIL sensitivity in hepatocytes. PLoS One 4:e4623
Shepard, Brett D; De Forni, Davide; McNamara, David R et al. (2008) Beneficial effect of TRAIL on HIV burden, without detectable immune consequences. PLoS One 3:e3096
Bren, Gary D; Whitman, Joe; Cummins, Nathan et al. (2008) Infected cell killing by HIV-1 protease promotes NF-kappaB dependent HIV-1 replication. PLoS One 3:e2112