Because of their shared routes of transmission, HCV coinfection with HIV is remarkably frequent in the U.S., particularly among injection drug users (IDU). With the success of HAART, traditional opportunistic infections among HIV-infected persons have been replaced by end stage liver disease due to viral hepatitis, particularly HCV, as the second leading cause of death among HIV-infected persons today. The most important clinical features of HCV in HIV-infected persons compared to HIV-negative persons are (1) its higher rates of persistence; (2) low rates of response to interferon (IFN) based antiviral therapy;and (3) accelerated hepatic fibrosis progression. Our efforts to date to decipher the mechanistic underpinnings of accelerated HCV liver disease progression in HIV coinfection have yielded fruitful insights, including discovery of the convergent effects of both infections on profibrogeni cytokine (TGF- 1) production in hepatocytes through their independent effects on generation of oxidative stress, as well as description of the cooperative interactions between these two viruses in promoting hepatocyte apoptosis. These findings have been drawn from necessarily limited (monoculture) model systems, and, while they represent meaningful advances, cannot fully recapitulate human disease. For instance, it is known that other cell types contribute significantly to hepatic fibrogenesis, particularly the Kupffer cell. Moreover, a central derangement in HIV infection is increased microbial translocation, which may contribute significantly to hepatic fibrogenesis. Therefore, the goals of the current proposal are to (1) extend our studies to evaluate the specific contributions of HCV and HIV to fibrosis progression for the first time in in vivo models; (2) evaluate the contribution of microbial translocation to fibrogenesis; and (3) evaluate the effect of antiretroviral therapy on cooperative HCV-HIV fibropathogenesis. To accomplish these goals, we will employ two novel model systems, including (1) a microfluidic coculture systems that deploys hepatocyte, macrophage, and hepatic stellate cell lines that are equipped with an array of cellular reporters that permit dynamic analysis of the events surrounding HCV and/or HIV infection, and (2) a newly described humanized mouse model that supports both HCV and HIV infections and recapitulates hepatic fibrosis. These studies will have a very high likelihood of identifying key processes that drive th observed hepatic pathophysiologic changes in coinfection. They will also, by virtue of identifying and prioritizing molecular targets that contribute to pathogenesis, have a high likelihood of revealing new therapeutic strategies to retard the observed accelerated liver disease progression in coinfection. The proposed studies will be of high impact, since they will greatly aid our efforts to develop effective interventions to halt or reverse liver disease progression among HCV-HIV coinfected persons.

Public Health Relevance

Persons harboring chronic hepatitis C have an accelerated course of liver disease progression if they are also infected with HIV. This results in higher rate of liver failure, death, and need for liver transplantation, making liver disease the second leadin cause of death among HIV-infected persons. Using a truly unique set of tools, including a humanized mouse model that supports both HCV and HIV infections and develops liver scarring, we hope to identify the key interactions that underlie the basis for accelerated liver disease and new approaches to slowing or reversing liver scarring.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56DK098079-01
Application #
8548054
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Doo, Edward
Project Start
2012-09-24
Project End
2013-08-31
Budget Start
2012-09-24
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$506,181
Indirect Cost
$198,308
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Duan, Xiaoqiong; Li, Shilin; Holmes, Jacinta A et al. (2018) MicroRNA 130a Regulates both Hepatitis C Virus and Hepatitis B Virus Replication through a Central Metabolic Pathway. J Virol 92:
Nakagawa, Shigeki; Wei, Lan; Song, Won Min et al. (2016) Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. Cancer Cell 30:879-890
Chusri, Pattranuch; Kumthip, Kattareeya; Hong, Jian et al. (2016) HCV induces transforming growth factor ?1 through activation of endoplasmic reticulum stress and the unfolded protein response. Sci Rep 6:22487
Yin, Peiqi; Hong, Zhi; Yang, Xiaojie et al. (2016) A role for retromer in hepatitis C virus replication. Cell Mol Life Sci 73:869-81
Zhou, Chan; York, Samuel R; Chen, Jennifer Y et al. (2016) Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins. Genome Med 8:31
Salloum, Shadi; Holmes, Jacinta A; Jindal, Rohit et al. (2016) Exposure to human immunodeficiency virus/hepatitis C virus in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types. Hepatology 64:1951-1968
Bility, Moses T; Nio, Kouki; Li, Feng et al. (2016) Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation. Sci Rep 6:39520
Lin, Wenyu; Zhu, Chuanlong; Hong, Jian et al. (2015) The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing. J Hepatol 62:1024-32
Zhu, Chuanlong; Xiao, Fei; Hong, Jian et al. (2015) EFTUD2 Is a Novel Innate Immune Regulator Restricting Hepatitis C Virus Infection through the RIG-I/MDA5 Pathway. J Virol 89:6608-18
King, Lindsay Y; Canasto-Chibuque, Claudia; Johnson, Kara B et al. (2015) A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut 64:1296-302

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