Expression of HCV Structural Proteins Impairs IFN-Mediated Antiviral Response

Keskinen, Päivi; Melén, Krister; Julkunen, Ilkka

doi:10.1006/viro.2002.1527

Cited by 20 publications

(13 citation statements)

References 44 publications

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“…Viral protein E2 is known to inhibit PKR activities, which, in turn, might result in the attenuated antiviral effects of IFN-␣ (36). Furthermore, Keskinen et al (19) showed that expression of HCV structural proteins impaired the antiviral activities of IFNs. Thus, expression of HCV structural proteins might have compromised the anti-HCV activity of IFN-␣.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Hwang

Tsai

Lee

et al. 2004

Antimicrob Agents Chemother

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Hepatitis C virus (HCV) isApproximately 170 million individuals worldwide suffer from chronic hepatitis C virus (HCV) infection (38). Although the acute phase of infection is usually associated with mild symptoms, most patients acquire a persistent infection that frequently leads to chronic liver diseases, including cirrhosis and hepatocellular carcinoma (21,25). At present, alpha interferon (IFN-␣) in combination with ribavirin or a polyethylene glycolmodified form of IFN-␣ in combination with ribavirin is the only recommended therapy. IFN-based therapies have shown only limited efficacy and are unsuitable for certain patient populations, although IFN-based therapies are relatively more efficacious against genotypes 2 and 3 than against genotype 1 (13,30,31,34). The limited efficacy against genotype 1 and the poor tolerability of IFN-based therapies warrant the search for more effective medicines to combat HCV infection.HCV is the only member of the genus Hepacivirus that belongs to the family Flaviviridae. HCV contains a single-stranded, positive-sense RNA genome of approximately 9.5 kb which encodes a unique polyprotein (10). The polyprotein precursor is co-and posttranslationally processed by cellular and viral proteases to yield the mature structural and nonstructural proteins, arranged in the sequence NH 2 -C-E1-E2-P7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH. The inability to efficiently propagate HCV in cell culture has impeded the development of drugs against this virus. This obstacle was overcome, to a degree, by the recent development of a bicistronic subgenomic HCV replicon in Huh-7 cells (5, 26). These subgenomic replicon systems have greatly facilitated studies of HCV replication.The pharmaceutical industry has also been using such replication systems to screen for anti-HCV drugs (2).A reporter gene that can be used to monitor HCV RNA replication by simply measuring the enzymatic activity of secreted alkaline phosphatase (SEAP) in the culture medium has been developed previously (23). In this study, we focused on screening a set of marketed drugs, including drugs not approved for antiviral indications. Here, we report on the discovery that As 2 O 3 is a potent anti-HCV agent. We also showed that As 2 O 3 and IFN-␣ have synergistic antiviral effects when they are used together. Recently, the U.S. Food and Drug Administration approved As 2 O 3 for use for the treatment of acute promyelocytic leukemia (APL) (8, 37). The possibility that As 2 O 3 or its analogues may be used for the treatment of HCV infections is discussed. MATERIALS AND METHODSCompound collection. The compounds tested were mainly from The Genesis Plus Collection (MicroSource Discovery Systems, Inc., Gaylordsville, Conn.). The 960 compounds in this library are primarily U.S. Food and Drug Administration-approved compounds. An alphabetical list of the compounds can be found at the MicroSource Discovery Systems website (http://www.msdiscovery .com/genplus3.html). In addition, several other drugs used for the treatment of HCV infections, including...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Hwang

Tsai

Lee

et al. 2004

Antimicrob Agents Chemother

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“…The titer of the virus stock was 1.2 × 10 9 plaque‐forming units (PFU)/ml. Vesicular stomatis virus stocks (Indiana strain) were grown in HEp2F cells and the stock virus had a titer of 4 × 10 6 PFU/ml 10, 11. Self‐inactivating (SIN) lentivirus vector HPT‐GFP (1.4 × 10 8 infectious units (IU)/ml) (a kind gift from Professor Didier Trono, University of Geneva, Switzerland) was used in lentiviral transductions.…”

Section: Methodsmentioning

confidence: 99%

Type I interferon response against viral and non‐viral gene transfer in human tumor and primary cell lines

Rautsi

Lehmusvaara

Salonen

et al. 2006

The Journal of Gene Medicine

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The non-viral gene transfer methods have gained more interest in recent years due to their better safety profiles when compared to their viral counterparts. However, the efficiency of non-viral gene transfer is well below those reached by viral vector systems. The type I interferon response induced by non-viral methods may in part contribute to this inefficiency, while most currently used viral gene transfer vectors fail to induce or are able to suppress type I IFN response.

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“…Vaccina virus encodes multiple genes that antagonize with the action of type I IFN (10). Also, other viruses like influenza A virus (11,12), rotavirus (13), rabies virus (14), Ebola virus (15), HSV type 1 (16), Epstein-Barr virus (17), hepatitis C virus (18)(19)(20)(21)(22), and adenovirus (23)(24)(25) have evolved means to downregulate the IFN response at different phases of infection. During retroviral infections, such as HIV, SIV, or Friend retro virus (FV), the type I IFN response is quite weak.…”

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confidence: 99%

Polyinosinic-Polycytidylic Acid Treatment of Friend Retrovirus-Infected Mice Improves Functional Properties of Virus-Specific T Cells and Prevents Virus-Induced Disease

Gibbert

Dietze

Zelinskyy

et al. 2010

The Journal of Immunology

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The induction of type I IFN is the most immediate host response to viral infections. Type I IFN has a direct antiviral activity mediated by antiviral enzymes, but it also modulates the function of cells of the adaptive immune system. Many viruses can suppress type I IFN production, and in retroviral infections, the initial type I IFN is weak. Thus, one strategy of immunotherapy in viral infection is the exogenous induction of type I IFN during acute viral infection by TLR ligands. Along these lines, the TLR3/MDA5 ligand polyinosinic-polycytidylic acid [poly(I:C)] has already been used to treat viral infections. However, the immunological mechanisms underlying this successful therapy have not been defined until now. In this study, the Friend retrovirus (FV) mouse model was used to investigate the mode of action of poly(I:C) in antiretroviral immunotherapy. Postexposure, poly(I:C) treatment of FV-infected mice resulted in a significant reduction in viral loads and protection from virus-induced leukemia. This effect was IFN dependent because type I IFN receptor-deficient mice could not be protected by poly(I:C). The poly(I:C)-induced IFN response resulted in the expression of antiviral enzymes, which suppressed FV replication. Also, the virus-specific T cell response was augmented. Interestingly, it did not enhance the number of virus-specific CD4+ and CD8+ T cells, but rather the functional properties of these cells, such as cytokine production and cytotoxic activity. The results demonstrate a direct antiviral and immunomodulatory effect of poly(I:C) and, therefore, suggests its potential for clinical treatment of retroviral infections.

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Expression of HCV Structural Proteins Impairs IFN-Mediated Antiviral Response

Cited by 20 publications

References 44 publications

Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Inhibition of Hepatitis C Virus Replication by Arsenic Trioxide

Type I interferon response against viral and non‐viral gene transfer in human tumor and primary cell lines

Polyinosinic-Polycytidylic Acid Treatment of Friend Retrovirus-Infected Mice Improves Functional Properties of Virus-Specific T Cells and Prevents Virus-Induced Disease

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