Innate immune responses in hepatitis C virus infection

Li, Kui; Lemon, Stanley M.

doi:10.1007/s00281-012-0332-x

Cited by 71 publications

(74 citation statements)

References 186 publications

(295 reference statements)

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“…Actually, a minority of ISGs, including PRRs, IRFs, the OASRNase L system, and the IFITM family members are relatively well characterized in antiviral immunity (43,44). However, the working mechanisms of these known ISGs are entirely different from that equipped by ISG12a with functions to mediate degradation of viral protein.…”

Section: Discussionmentioning

confidence: 99%

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Xue

Yang

Wang

et al. 2016

J Virol

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Interferons (IFNs) restrict various kinds of viral infection via induction of hundreds of IFN-stimulated genes (ISGs), while the functions of the majority of ISGs are broadly unclear. Here, we show that a high-IFN-inducible gene, ISG12a (also known as IFI27), exhibits a nonapoptotic antiviral effect on hepatitis C virus (HCV) infection. Viral NS5A protein is targeted specifically by ISG12a, which mediates NS5A degradation via a ubiquitination-dependent proteasomal pathway. K374R mutation in NS5A domain III abrogates ISG12a-induced ubiquitination and degradation of NS5A. S-phase kinase-associated protein 2 (SKP2) is identified as an ubiquitin E3 ligase for NS5A. ISG12a functions as a crucial adaptor that promotes SKP2 to interact with and degrade viral protein. Moreover, the antiviral effect of ISG12a is dependent on the E3 ligase activity of SKP2. These findings uncover an intriguing mechanism by which ISG12a restricts viral infection and provide clues for understanding the actions of innate immunity. IMPORTANCE Upon virus invasion, IFNs induce numerous ISGs to control viral spread, while the functions of the majority of ISGs are broadlyunclear. The present study shows a novel antiviral mechanism of ISGs and elucidated that ISG12a recruits an E3 ligase, SKP2, for ubiquitination and degradation of viral protein and restricts viral infection. These findings provide important insights into exploring the working principles of innate immunity.

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Section: Discussionmentioning

confidence: 99%

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Xue

Yang

Wang

et al. 2016

J Virol

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“…The ability of HCV to productively infect DCs is controversial (57), but it is possible that phagocytosis of apoptotic HCV-infected hepatocytes and expression of HCV proteins are enough to disrupt DC function. In addition, the HCV NS3/4A protease has been shown to block signaling through TLR3, TLR4, and retinoic acid inducible gene I (RIG-I) and, consequently, block IFN-␤ production by infected cells and in infected tissues (58,59). …”

Section: Discussionmentioning

confidence: 99%

Sustained Hyperresponsiveness of Dendritic Cells Is Associated with Spontaneous Resolution of Acute Hepatitis C

Pelletier

Bédard

Said

et al. 2013

J Virol

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Some studies have reported that dendritic cells (DCs) may be dysfunctional in a subset of patients with chronic hepatitis C virus (HCV) infection. However, the function of DCs during acute HCV infection and their role in determining infectious outcome remain elusive. Here, we examined the phenotype and function of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) during acute HCV infection. Three groups of injection drug users (IDUs) at high risk of HCV infection were studied: an uninfected group, a group with acute HCV infection with spontaneous resolution, and a group with acute infection with chronic evolution. We examined the frequency, maturation status, and cytokine production capacity of DCs in response to the Toll-like receptor 4 (TLR4) and TLR7/8 ligands lipopolysaccharide (LPS) and single-stranded RNA (ssRNA), respectively. Several observations could distinguish HCV-negative IDUs and acute HCV resolvers from patients with acute infection with chronic evolution. First, we observed a decrease in the frequency of mature CD86؉ , programmed death-1 receptor ligand-positive (PDL1 ؉ ), and PDL2 ؉ pDCs. This phenotype was associated with the increased sensitivity of pDCs from resolvers and HCV-negative IDUs versus the group with acute infection with chronic evolution to ssRNA stimulation in vitro. Second, LPS-stimulated mDCs from resolvers and HCV-negative IDUs produced higher levels of cytokines than mDCs from the group with acute infection with chronic evolution. Third, mDCs from all patients with acute HCV infection, irrespective of their outcomes, produced higher levels of cytokines during the early acute phase in response to ssRNA than mDCs from healthy controls. However, this hyperresponsiveness was sustained only in spontaneous resolvers. Altogether, our results suggest that the immature pDC phenotype and sustained pDC and mDC hyperresponsiveness are associated with spontaneous resolution of acute HCV infection.A minor fraction of individuals infected with the hepatitis C virus (HCV) eliminate the virus spontaneously, while the majority develop persistent infection, which may lead to chronic liver diseases (1). Spontaneous resolution of acute HCV infection is associated with the development of a robust and sustained HCV-specific CD4 and CD8 T cell response (2). In contrast, such responses are weak, inefficient, or transient in individuals who develop chronic infection. Several mechanisms underlying this immune failure have been previously described. First, escape mutations in epitopes targeted by virus-specific CD8 ϩ T cells can occur early during acute HCV infection, and this correlates with virus persistence (3-6). Second, failure of HCV-specific CD4 helper T cells to proliferate and produce cytokines was associated with viral recurrence and persistence. This loss of CD4 T cell help may compromise the function of virus-specific CD8 T cells and contribute to the development of suboptimal or exhausted CD8 ϩ T cells (7-13). Dendritic cells (DCs) are the most potent antigen-presenting cells in the body, and ...

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“…These features likely facilitate persistent HCV infections in humans by protecting the genome from degradation by innate antiviral defenses (20,21). Two elements of this defense are RNase L, which cleaves in single-stranded regions (22), and diverse double-stranded RNA-induced antiviral immune responses (23).…”

mentioning

confidence: 99%

Functionally conserved architecture of hepatitis C virus RNA genomes

Mauger¹,

Golden

Yamane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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128

190

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Hepatitis C virus (HCV) infects over 170 million people worldwide and is a leading cause of liver disease and cancer. The virus has a 9,650-nt, single-stranded, messenger-sense RNA genome that is infectious as an independent entity. The RNA genome has evolved in response to complex selection pressures, including the need to maintain structures that facilitate replication and to avoid clearance by cell-intrinsic immune processes. Here we used highthroughput, single-nucleotide resolution information to generate and functionally test data-driven structural models for three diverse HCV RNA genomes. We identified, de novo, multiple regions of conserved RNA structure, including all previously characterized cisacting regulatory elements and also multiple novel structures required for optimal viral fitness. Well-defined RNA structures in the central regions of HCV genomes appear to facilitate persistent infection by masking the genome from RNase L and double-stranded RNA-induced innate immune sensors. This work shows how structure-first comparative analysis of entire genomes of a pathogenic RNA virus enables comprehensive and concise identification of regulatory elements and emphasizes the extensive interrelationships among RNA genome structure, viral biology, and innate immune responses.RNA structure | evolution | motif discovery | functional validation H epatitis C virus (HCV) currently infects over 170 million people. There is no vaccine, and therapy, generally involving treatment with IFN and ribavirin, is often ineffective (1). Efficacious anti-HCV therapeutics are becoming available (2), but the extent to which they will mitigate the hepatitis C disease burden remains to be seen. Roughly 70% of acutely infected individuals fail to clear the virus and become lifelong HCV carriers, at risk for progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (3).HCV genomes are single-stranded, ∼9,650-nt, messengersense RNA molecules (4). The naked RNA initiates autonomous replication when transfected into cells and establishes chronic HCV infection in chimpanzees (5, 6). The HCV genomic RNA carries genetic information at two levels: a single large ORF encodes viral proteins and complex RNA structural elements regulate the viral replication cycle (4). Viral replication begins when conserved RNA elements in the 5′ UTR bind the 40S ribosome subunit and recruit essential translation factors (7). Translation produces a viral polyprotein that is cleaved by cellular and viral proteases to generate 10 viral proteins (4). The HCV genome is replicated through a negative-strand RNA intermediate by a viral RNA-dependent RNA polymerase (NS5B) in a process controlled by conserved RNA elements (8-17).The HCV genomic RNA is physically compact (18) and highly structured (19). These features likely facilitate persistent HCV infections in humans by protecting the genome from degradation by innate antiviral defenses (20,21). Two elements of this defense are RNase L, which cleaves in single-stranded regions (22), and diverse double...

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Innate immune responses in hepatitis C virus infection

Cited by 71 publications

References 186 publications

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Sustained Hyperresponsiveness of Dendritic Cells Is Associated with Spontaneous Resolution of Acute Hepatitis C

Functionally conserved architecture of hepatitis C virus RNA genomes

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