Hepatitis C virus (HCV) is a major public health problem with more than 170 millions people are currently infected. Most infections become chronic often leading to liver cirrhosis and cancer. In the United States 10,000 to 20,000 deaths a year are caused by chronic HCV infection. It is the most common cause of liver transplantation. It is now believed that long-standing chronic inflammation secondary to HCV infection is the main cause of hepatocellular carcinoma. The mechanisms underlying the development of long-lasting chronic inflammation and cancer are not well understood. Current therapy for chronic HCV infection, a combination of IFN-a and ribavirin, but only half of the patients can get rid of the virus infection by this regimen. The reasons why HCV infection leads to a high rate of chronic infection in human and often develops resistance to interferon therapy are not clear. The overall goals of this proposal are to understand the mechanisms of interferon action and resistance in chronic HCV infection, and develop alternative antiviral strategies to inhibit HCV replication. During the last couple of years our research has generated the following evidences: (i). We have developed interferon-resistant replicon cell lines and determined that a defect in the Jak-Stat signaling pathway can lead to low-level activation of ISRE promoter (IFN-promoter) and interferon resistance phenotypes. (ii). We have published data showing that IFN-a, IFN-? and IFN-? each inhibits HCV replication. This inhibitory effect of interferon is at the level of ribosome loading to the 5'UTR sequences used by the virus to translate its genome by an internal ribosome entry site (IRES) dependent mechanism. (iii). Recently, we have reported that small interfering RNA (siRNA) targeted to the IRES region that can inhibit translation of six different HCV genotypes. Based on these preliminary studies our hypothesis is that the expression of the Jak-Stat signaling molecules that control the transcription of interferon-inducible genes varies among infected hepatocytes in the liver. Hepatocytes with a defective Jak-Stat signaling escape interferon action at the level of IRES translation leading to chronic persistent virus replication. We propose that encapsulation of siRNA-74 into nanoparticles by the use of biodegradable polymers will efficiently deliver siRNA to the hepatocytes and may provide a novel therapeutic strategy for chronic HCV patients who are non-responders to interferon. To test our hypothesis we have developed three Specific Aims.
In Specific Aim 1, we will investigate hepatic resistance to IFN-alpha in HCV chronically infected humans.
In Specific Aim 2, we will investigate the antiviral mechanisms of IFN-alpha against hepatitis C virus.
In Specific Aim 3, we will formulate biodegradable nanocapsules as a non-viral method to deliver siRNA to inhibit viral target of interferon to overcome mechanisms of resistance. If these experiments are successful then it will increase our understanding on the mechanisms of interferon action and resistance against chronic HCV. This research will potentially leads to an innovative therapeutic strategy for chronic hepatitis C patients not responding to interferon therapy. Public Health Relevance: Chronic hepatitis C virus infection is the major cause of liver cancer in the United States. This research proposal intends to develop intracellular immunization strategy to inhibit HCV. If these experiments are successful it can potentially lead to a therapy for chronic HCV infection and prevent liver cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tulane University
Schools of Medicine
New Orleans
United States
Zip Code
Bao, Lili; Chandra, Partha K; Moroz, Krzysztof et al. (2014) Impaired autophagy response in human hepatocellular carcinoma. Exp Mol Pathol 96:149-54
Gunduz, Feyza; Mallikarjun, Chaithanya; Balart, Luis A et al. (2014) Interferon alpha induced intrahepatic pSTAT1 inversely correlate with serum HCV RNA levels in chronic HCV infection. Exp Mol Pathol 96:36-41
McCarthy, Michelle; Auda, Gregory; Agrawal, Suchi et al. (2014) In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer. Exp Mol Pathol 97:6-15
Chandra, Partha K; Gunduz, Feyza; Hazari, Sidhartha et al. (2014) Impaired expression of type I and type II interferon receptors in HCV-associated chronic liver disease and liver cirrhosis. PLoS One 9:e108616
Chandra, Partha K; Bao, Lili; Song, Kyoungsub et al. (2014) HCV infection selectively impairs type I but not type III IFN signaling. Am J Pathol 184:214-29
Panigrahi, Rajesh; Hazari, Sidhartha; Chandra, Sruti et al. (2013) Interferon and ribavirin combination treatment synergistically inhibit HCV internal ribosome entry site mediated translation at the level of polyribosome formation. PLoS One 8:e72791
Kundu, Anup K; Chandra, Partha K; Hazari, Sidhartha et al. (2012) Stability of lyophilized siRNA nanosome formulations. Int J Pharm 423:525-34
Kundu, Anup K; Chandra, Partha K; Hazari, Sidhartha et al. (2012) Development and optimization of nanosomal formulations for siRNA delivery to the liver. Eur J Pharm Biopharm 80:257-67
Bao, Lili; Hazari, Sidhartha; Mehra, Smriti et al. (2012) Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298. Am J Pathol 180:2490-503
Bao, Lili; Haque, Aliyya; Jackson, Kamilah et al. (2011) Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model. Am J Pathol 178:838-52

Showing the most recent 10 out of 17 publications