HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling

Chandra, Partha K.; Bao, Lili; Song, Kyoungsub; Aboulnasr, Fatma; Baker, Darren P.; Shores, Nathan J.; Wimley, William C.; Liu, Shuanghu; Hagedorn, Curt H.; Fuchs, Serge Y.; Wu, Tong; Balart, Luis A.; Dash, Srikanta

doi:10.1016/j.ajpath.2013.10.005

Cited by 62 publications

(88 citation statements)

References 41 publications

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“…Accumulation of large amounts of viral proteins during persistent replication induces a stress response in infected PHHs. Prior studies have shown that the UPR was either partially activated or suppressed to attenuate ER‐stress‐mediated hepatocellular apoptosis using transformed hepatoma cells (Huh‐7.5) soon after virus infection 9, 10. It is unclear whether persistent HCV replication induced chronic or adaptive ER stress in untransformed hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Over the past several years, many investigators, including our own, showed that HCV‐associated ER stress induced an autophagy response, which results in impaired host innate immunity through blocking endogenous IFN production7, 9 and also escapes from exogenously added IFN‐α and ribavirin (RBV)‐based antiviral therapy through degradation of interferon‐alpha receptor 1 and RBV transporter 10, 11. In this report, we found that HCV infection induces chaperone‐mediated autophagy (CMA) as a cell survival mechanism to avoid the ER‐stress response.…”

Section: Introductionmentioning

confidence: 99%

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Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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“…The IL28B gene locus encodes for IFN-3, a member of type III IFN family (Chandra et al, 2014). Many studies have demonstrated that the presence of a single nucleotide polymorphism (SNP) at the IL28B locus is associated with a reduced response to Peg IFN/RBV therapy and also an increased prevalence of PBMC infection (Amanzada et al, 2011;Youssef et al, 2013).…”

Section: Potential Pathogenic Mechanisms Resulting In An Ocimentioning

confidence: 99%

Occult Hepatitis C Infection and its Clinical Relevance in Lymphoproliferative Disorders

Agha¹,

Mashad²,

Mofreh³

2017

Int.J.Curr.Microbiol.App.Sci

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“…The Renilla luciferase reporter-based pJFH-⌬V3-Rluc clone used in our experiment was described previously (22) Interferon and RBV treatment and HCV quantification. To study the mechanisms of HCV clearance by RBV, we established a stable and persistently HCV-infected cell culture system with Huh-7.5 cells that releases infectious virus particles and enables quantification of HCV replication by the measurement of Renilla luciferase, Western blotting, and immunostaining (20). RBV treatment of HCV-infected cultures was performed in six-well tissue culture plates (Costar; Corning, Tewksbury, MA) in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we reported that a combined HCV-induced endoplasmic reticulum (ER) stress and autophagy response downregulates the expression of IFN-␣ receptor 1, which is why HCV replication in a persistently infected cell culture is not completely inhibited by IFN-␣ (20,21). In this study, we investigated virus and host cell interactions that impair RBV antiviral activity in a persistently HCV-infected cell culture system.…”

mentioning

confidence: 99%

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

Panigrahi

Chandra

Ferraris

et al. 2015

J Virol

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Ribavirin (RBV) continues to be an important component of interferon-free hepatitis C treatment regimens, as RBV alone does not inhibit hepatitis C virus (HCV) replication effectively; the reason for this ineffectiveness has not been established. In this study, we investigated the RBV resistance mechanism using a persistently HCV-infected cell culture system. The antiviral activity of RBV against HCV was progressively impaired in the persistently infected culture, whereas interferon lambda 1 (IFN-1), a type III IFN, showed a strong antiviral response and induced viral clearance. We found that HCV replication in persistently infected cultures induces an autophagy response that impairs RBV uptake by preventing the expression of equilibrative nucleoside transporter 1 (ENT1). The Huh-7.5 cell line treated with an autophagy inducer, Torin 1, downregulated membrane expression of ENT1 and terminated RBV uptake. In contrast, the autophagy inhibitors hydroxychloroquine (HCQ), 3-methyladenine (3-MA), and bafilomycin A1 (BafA1) prevented ENT1 degradation and enhanced RBV antiviral activity. The HCV-induced autophagy response, as well as treatment with Torin 1, degrades clathrin heavy chain expression in a hepatoma cell line. Reduced expression of the clathrin heavy chain by HCV prevents ENT1 recycling to the plasma membrane and forces ENT1 to the lysosome for degradation. This study provides a potential mechanism for the impairment of RBV antiviral activity in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy for improving RBV antiviral activity against HCV infection. IMPORTANCEThe results from this work will allow a review of the competing theories of antiviral therapy development in the field of HCV virology. Ribavirin (RBV) remains an important component of interferon-free hepatitis C treatment regimens. The reason why RBV alone does not inhibit HCV replication effectively has not been established. This study provides a potential mechanism for why RBV antiviral activity is impaired in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy to increase RBV antiviral activity against HCV infection. Therefore, it is anticipated that this work would generate a great deal of interest, not only among virologists but also among the general public. H epatitis C virus (HCV) is estimated to infect Ͼ185 million people worldwide (1). Infection by HCV leads to a high likelihood of chronic liver disease, which often progresses to liver cirrhosis and hepatocellular carcinoma; HCV is therefore a major public health problem. Interferon alpha (IFN-␣) and ribavirin (RBV) (a guanosine analogue) have been used as standard therapy for chronic HCV infection for over a decade, with a sustained virologic response rate of 50% for genotype 1a virus. In 2011, two HCV-specific direct-acting antivirals (DAAs) targeting to NS3 protease (telaprevir and boceprevir) received FDA appro...

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HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling

Cited by 62 publications

References 41 publications

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Occult Hepatitis C Infection and its Clinical Relevance in Lymphoproliferative Disorders

Persistent Hepatitis C Virus Infection Impairs Ribavirin Antiviral Activity through Clathrin-Mediated Trafficking of Equilibrative Nucleoside Transporter 1

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