Advancing Understanding of Mechanisms of Hepatitis-Related Liver Disease Raymond Chung, MD

Overview

Raymond Chung, MD, Director of Hepatology and Vice Chief of Gastroenterology, leads an NIH-funded Center for Human Immunology U19 Program, a consortium of eight projects centered on understanding the basis for the persistence of hepatitis C virus, an infection with a remarkable tendency to become chronic.

His laboratory has been committed to uncovering the strategies employed by hepatitis C virus to ensure its persistence in the liver, and the basis by which the infection causes liver scarring and cancer.

These studies include investigations into the basis for host genetic predispositions to successful responses to therapy with interferon.

His group has also been exploring the basis for HCV’s disruptive effects on lipid metabolism and insulin handling by the liver that lead to alterations in cholesterol levels and increased risk for diabetes.

Dr. Chung also leads the Mass General site of the NIH Hepatitis B Research Network, which is committed to long term study of optimal antiviral treatment strategies to prevent cirrhosis and liver cancer in persons chronically infected with this hepatitis virus.

Our laboratory projects include:

• Understanding how and why HIV cooperates with HCV to cause more accelerated and severe liver disease than those persons with HCV alone
• Identifying the host cellular proteins that facilitate the replication of HCV and exploiting knowledge of these proteins to design innovative treatments for HCV
• Identifying the principal genes and proteins responsible for interferon’s known antiviral effects against HCV
  Investigation of the mechanisms of HCV-associated insulin resistance
• Exploration of the antiviral activity of statins against HCV
• A pilot clinical trial of naringenin (a compound found in grapefruit) as a potential antiviral drug against HCV
• Genetic studies to identify predispositions to fatty liver disease
• Development of biomarkers to identify those persons with more severe, progressive forms of fatty liver
• Development of biomarkers and prediction rules to identify persons with acute liver failure who are at highest risk for mortality or need for liver transplantation

Research Projects

Our laboratory has been focused on the mechanisms of HCV persistence and pathogenesis.

Hepatitis C virus infects 170 million persons worldwide and is remarkable for its predilection for chronicity. It is also a leading cause of chronic liver disease, liver cancer, and is the leading reason for liver transplantation.

We have focused our efforts in development of model systems supportive of HCV replication, elucidating some of the many mechanisms by which viral proteins subvert innate antiviral immunity, particularly type I IFN signaling.

We have focused on the actions of HCV core protein, which induces the selective degradation and inhbition of STAT1 phosphorylation.

We are also studying suppressors of cytokine signaling (particularly SOCS3) and their interaction with IFN signaling in chronic HCV.

Identification of the mechanisms underlying control of HCV by interferon alfa and IL28B

Interferon alfa, a type I IFN, exerts its broad antiviral effect through the induction of hundreds of host interferon stimulated genes (ISGs). However, the key genes operative against HCV are unknown.

We have been using functional genomic approaches to elucidate the key genes responsible for type I IFN action, in the hopes of refining treatments that retain interferon’s potency without producing the numerous systemic adverse effects that limit interferon therapy.

In separate studies, a genome wide association study (GWAS) has identified that a polymorphism in the IL28B (IFN lambda-3) locus that is a powerful predictor of success with interferon alfa therapy.

We are now exploring the functional basis for this finding using HCV infection models. By identifying the host mediators of IL28B action, we hope to further optimize treatment approaches to HCV.

High throughput screening approaches to the identification of key cellular regulators of HCV replication and persistence

Another avenue our laboratory has taken is a high throughput screen for small molecules that regulate HCV infection using a tractable replicon model.

To accomplish this, we have successfully employed two large scale screening strategies. Using a compound screening library, we have identified a number of small molecules that inhibit HCV replication and have successfully performed target identification to clarify their host cell targets.

Similarly, we have used a whole genome siRNA library approach and identified several dozen host genes that participate in HCV replication.

These include proteins involved in the secretory pathway and facilitation of intracellular lipid transport.

We believe that these approaches will add to our understanding of the underpinnings of HCV replication and lead to novel strategies to interrupt its lifecycle.

Unraveling the mechanisms underlying the acceleration of HCV pathogenesis by HIV coinfection

We have also been interested in understanding the basis for the observation of more progressive HCV-related liver disease in HIV-infected persons, despite the lack of liver tropism for HIV.

We have found that HIV and its envelope protein gp120 can upregulate HCV replication through chemokine receptor-dependent means, and that this upregulation of HCV replication is TGF-b mediated.

This finding may help to explain both the increased levels of HCV replication observed in HIV, but also the acceleration of hepatic fibrosis observed in coinfection.

We are currently studying the mechanisms by which viral proteins induce TGF-beta and, in turn, contribute to hepatic fibrosis.

We have also found that HIV can promote hepatocyte apoptosis, highlighting another avenue for its contribution to accelerated pathogenesis.

Publications

1. Lin W, Choe WH, Hiasa Y, Kamegaya Y, Blackard JT, Schmidt EV, Chung RT. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology. 2005 Apr;128(4):1034-41.
2. Lin W, Kim SS, Yeung E, Kamegaya Y, Blackard JT, Kim KA, Holtzman MJ, Chung RT. Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol 2006;80:9226-35.
3. O’Leary JG, Chan J, McMahon C, Chung RT. Atorvastatin Does Not Exhibit Antiviral Activity Against HCV At Conventional Doses: A Pilot Clinical Trial. Hepatology 2007;45:895-898.
4. Kim SS, Peng LF, Lin W, Choe WH, Sakamoto N, Schreiber SL, Chung RT. A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. Gastroenterology 2007;132:311-20.
5. Lin W, Weinberg EM, Tai AW, Peng LF, Brockman MA, Kim KA, Kim SS, Borges CB, Shao RX, Chung RT. HIV Increases HCV Replication in a TGF-beta1-Dependent Manner. Gastroenterology. 2008;134(3):803-11.
6. Peng LF, Kim SS, Matchacheep S, Lei X, Su S, Lin W, Punguphan W, Choe WH, Sakamoto N, Ikeda M, Kato N, Beeler AB, Porco JA Jr, Schreiber SL, Chung RT Identification of Novel Epoxide Inhibitors of HCV Replication Using a High – Throughput Screen. Antimicrob Agents Chemother. 2007; 10:3756-59.
7. Rutherford AE, Hynan LS, Borges CB, Forcione DG, Blackard JT, Lin W, Gorman AR, Shaikh OS, Reuben A, Harrison E, Reddy KR, Lee WM, Chung RT; For the ALF Study Group. Serum Apoptosis Markers in Acute Liver Failure: A Pilot Study. Clin Gastroenterol Hepatol. 2007 Oct 27; 12:1477-53.
8. Chung RT, Gale M Jr, Polyak SJ, Lemon SM, Liang TJ, Hoofnagle JH; Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop. Hepatology. 2007; 47 (1): 306 –320.
9. Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, Lauwers GY, Kulu Y, Muzikansky A, Kuruppu D, Lanuti M, Goodwin JM, Azoulay D, Fuchs BC. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA. 2008; 299(1): 53-60.
10. Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008;47(5):1437-1445.
11. Kim KA, Lin W, Tai AW, Shao RX, Weinberg E, De Sa Borges CB, Bhan AK, Zheng H, Kamegaya Y, Chung RT. Hepatic SOCS3 expression is strongly associated with non-response to therapy and race in HCV and HCV/HIV infection. J Hepatology 2009;50:705-11.
12. Tai AW, Benita Y, Peng LF, Kim SS, Sakamoto N, Xavier RJ, Chung RT. A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. Cell Host Microbe. 2009;5:298-307
13. Delgado-Borrego A, Liu YS, Jordan SH, Agrawal S, Zhang H, Christofi M. Casson D, Cosimi, AB, Chung, RT. Prospective study of liver transplant recipients with HCV infection: Evidence for a causal relationship between HCV and insulin resistance. Liver Transpl. 2008 Jan 30; 14 (2): 193-201.
14. Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology. 2009;50:1030-7.
15. Delgado-Borrego A, Jordan SH, Negre B, Healey D, Lin W, Kamegaya Y, Christofi M, Ludwig DA, Lok AS, Chung RT; The HALT-C Trial Group. Reduction of Insulin Resistance with Effective Clearance of Hepatitis C Infection: Results from the Halt-C Trial. Clin Gastroenterol Hepatol. 2010 Feb 12. [Epub ahead of print].
16. Lin W, Tsai WL, Shao RX, Wu G, Peng LF, Barlow LL, Chung WJ, Zhang L, Zhao H, Jang JY, Chung RT. HCV regulates TGF-beta1 production through the generation of reactive oxygen species in an NFkappaB-dependent manner. Gastroenterology 2010 Mar 12. Epub ahead of print.
17. Delgado-Borrego A, Kamegaya Y, Jordan SH, Agrawal S, Valim C. Chung, RT. HCV synergizes with body weight in the promotion of insulin resistance. J Viral Hepat. 2010 May 20. [Epub ahead of print]
18. Jang JY, Shao RX, Lin W, Weinberg EM, Chung WJ, Tsai WL, Zhao H, Goto k, Zhang L, Mendez-Navarro J, Jilg N, Peng LF, Brockman MA, Chung RT. HIV infection increases HCV-induced hepatocyte apoptosis. Journal of Hepatology 2010; in press.
19. Shao RX, Zhang L, Peng LF, Sun E, Chung WJ, Jang JY, Tsai WL, Hyppolite G, Chung RT. Suppressor of Cytokine Signaling 3 (SOCS3) Suppresses Hepatitis C Virus Replication in an mTOR-dependent Manner. J Virol. 2010 Apr 7. Epub ahead of print.