Subversion of innate host antiviral strategies by the hepatitis C virus

Bode, Johannes G.; Brenndörfer, Erwin Daniel; Häussinger, Dieter

doi:10.1016/j.abb.2007.03.033

Cited by 35 publications

(34 citation statements)

References 160 publications

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“…HCV, a small, positive-sense, singlestranded RNA (ssRNA) virus that infects hepatocytes of the liver to cause liver inflammation (hepatitis), was the first virus reported to independently induce SOCS expression. Notably, HCV was already well known for its effective suppression of the host antiviral immune response, as evidenced by its propensity for establishing a chronic, lifelong infection in approximately 80% of cases (5). But the contribution of SOCS proteins to HCV's immune evasion arsenal was not described until 2003 by Bode et al (6).…”

Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 99%

Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

111

102

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Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

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Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 99%

Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

111

102

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“…This has been attributed to a combination of both host and viral factors, which include the immunosuppressive environment of the liver and the high mutation rate of the virus. Additionally, a number of viral proteins can suppress HCV-specific immune responses (20). There is evidence that both IL-10 and TGF-␤ are up-regulated in chronic HCV infection, and this may be associated with persistence and progression of the disease (21,22).…”

Section: R Ecently a Novel Lineage Of Cd4mentioning

confidence: 99%

Hepatitis C Virus-Specific Th17 Cells Are Suppressed by Virus-Induced TGF-β

Rowan

Fletcher

Ryan

et al. 2008

The Journal of Immunology

126

118

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IL-17-secreting T (Th17) cells play a protective role in certain bacterial infections, but they are major mediators of inflammation and are pathogenic in organ-specific autoimmune diseases. However, human Th17 cells appear to be resistant to suppression by CD4+CD25+FoxP3+ regulatory T cells, suggesting that they may be regulated by alternative mechanisms. Herein we show that IL-10 and TGF-β suppressed IL-17 production by anti-CD3-stimulated PBMC from normal individuals. TGF-β also suppressed IL-17 production by purified CD4+ T cells, whereas the inhibitory effect of IL-10 on IL-17 production appears to be mediated predominantly by its effect on APC. An examination of patients infected with hepatitis C virus (HCV) demonstrated that Ag-specific Th17 cells are induced during infection and that these cells are regulated by IL-10 and TGF-β. PBMC from HCV Ab-positive donors secreted IL-17, IFN-γ, IL-10, and TGF-β in response to stimulation with the HCV nonstructural protein 4 (NS4). Furthermore, NS4 induced innate TGF-β and IL-10 expression by monocytes from normal donors and at higher levels from HCV-infected patients. Neutralization of TGF-β, and to a lesser extent IL-10, significantly enhanced NS4-specific IL-17 and IFN-γ production by T cells from HCV-infected donors. Our findings suggest that both HCV-specific Th1 and Th17 cells are suppressed by NS4-induced production of the innate anti-inflammatory cytokines IL-10 and TGF-β. This may represent a novel immune subversion mechanism by the virus to evade host-protective immune responses. Our findings also suggest that TGF-β and IL-10 play important roles in constraining the function of Th17 cells in general.

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“…IFN signaling pathway as well as RNAi appear therefore to be subverted by HCV. Indeed, recent studies have demonstrated that the virus has developed strategies to bloc innate cell response and inhibit the antiviral effect of IFN (Bode et al, 2007;Gale & Foy, 2005;Randall & Goodbourn, 2008). Several HCV proteins interfere with the antiviral response of host cells to eventually repress the release of IFNβ, and with the IFNα signaling.…”

Section: Interferon Signaling Pathway and Viral Resistancementioning

confidence: 99%

“…In addition, NS5A induces the expression of IL8 which in turn negatively affects the antiviral effect of IFN (S. Girard et al, 2002;Khabar et al, 1997). While inhibiting the host innate or the IFN-induced defences, HCV proteins also protect infected cells from apoptosis (Bode et al, 2007). In this respect, HCV core protein has been shown to inhibit TNFα-or FAS-mediated activation of caspase 8, p21 and p53 expression, or to enhance Bcl-XL, Bcl2 and cyclin D1 expression or the Raf1/MAPK signaling pathways (Hassan et al, 2004;Saito et al, 2006).…”

Section: Interferon Signaling Pathway and Viral Resistancementioning

confidence: 99%

“…The acidic pH of endosomes (de Bouteiller et al, 2005) and association to the c-Src kinase favor dsRNA binding to and dimerisation of TLR3, and initiation of signal transduction, respectively. As reviewed by others (Bode et al, 2007;Matsumoto & Seya, 2008), TLR3 mediates signal transduction through an adaptor protein TICAM-1/TRIF. Once activated, TRIF recruits several proteins including TRAF3, TRAF6, NAP1 and RIP1 to form a multifunctional complex.…”

Section: Interferon-stimulating Gene Pathwaysmentioning

confidence: 99%

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Cellular models for the screening and development of anti-hepatitis C virus agents

Gondeau

Pichard-Garcia

Maurel

2009

Pharmacology & Therapeutics

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Investigations on the biology of hepatitis C virus (HCV) have been hampered by the lack of small animal models. Efforts have therefore been directed to designing practical and robust cellular models of human origin able to support HCV replication and production in a reproducible, reliable and consistent manner. Many different models based on different forms of virions and hepatoma or other cell types have been described including virus-like particles, pseudotyped particles, subgenomic and full length replicons, virion productive replicons, immortalised hepatocytes, fetal and adult primary human hepatocytes. This review focuses on these different cellular models, their advantages and disadvantages at the biological and experimental levels, and their respective use for evaluating the effect of antiviral molecules on different steps of HCV biology including virus entry, replication, particles generation and excretion, as well as on the modulation by the virus of the host cell response to infection.

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Subversion of innate host antiviral strategies by the hepatitis C virus

Cited by 35 publications

References 160 publications

Viral Exploitation of Host SOCS Protein Functions

Viral Exploitation of Host SOCS Protein Functions

Hepatitis C Virus-Specific Th17 Cells Are Suppressed by Virus-Induced TGF-β

Cellular models for the screening and development of anti-hepatitis C virus agents

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