The yin and yang of hepatitis C: synthesis and decay of hepatitis C virus RNA

Li, You; Yamane, Daisuke; Masaki, Takahiro; Lemon, Stanley M.

doi:10.1038/nrmicro3506

Cited by 35 publications

(40 citation statements)

References 154 publications

(267 reference statements)

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“…Indeed, across all treatments, very few cells exhibited a strand skew that favored negative strand vRNAs. This finding may suggest the negative strand is intrinsically less stable, a hypothesis that is consistent with previous reports suggesting the negative strand is less stable due to fewer interactions with miR-122 (11, 85) or other factors. However, since both NS5A inhibitors and HCV protease inhibitors have been shown to inhibit viral assembly and/or release (17, 86), the measured positive strand decline with these drugs (DCV and SIM) may be slowed somewhat by retention of otherwise-exported positive strand vRNAs.…”

Section: Discussionsupporting

confidence: 91%

“…The regulatory mechanisms governing the levels of HCV viral RNA and proteins in individual infected cells are of particular interest, as HCV is generally non-cytopathic and infects a minority of hepatocytes in the liver (11, 15). To this end, temporal profiling of patient viral loads upon treatment have enabled the development of detailed quantitative models for viral replication and antiviral efficacy at the patient level (16–21), but these studies do not provide the resolution necessary to measure viral and host transcriptional dynamics in single cells, which would provide unique information about the mechanism of host cell responses to infection and to antiviral therapies.…”

Section: Introductionmentioning

confidence: 99%

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Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies

et al. 2016

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Hepatitis C virus (HCV) is a positive single-stranded RNA virus of enormous global health importance, with direct-acting antiviral therapies replacing an immunostimulatory interferon-based regimen. The dynamics of HCV positive and negative-strand viral RNAs (vRNAs) under antiviral perturbations have not been studied at the single-cell level, leaving a gap in our understanding of antiviral kinetics and host-virus interactions. Here, we demonstrate quantitative imaging of HCV genomes in multiple infection models, and multiplexing of positive and negative strand vRNAs and host antiviral RNAs. We capture the varying kinetics with which antiviral drugs with different mechanisms of action clear HCV infection, finding the NS5A inhibitor daclatasvir to induce a rapid decline in negative-strand viral RNAs. We also find that the induction of host antiviral genes upon interferon treatment is positively correlated with viral load in single cells. This study adds smFISH to the toolbox available for analyzing the treatment of RNA virus infections.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies

et al. 2016

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“…Currently, no effective vaccine for HCV is available worldwide, which has greatly hampered the prevention of HCV infection and liver cancer due to hepatitis C. Although the treatment of HCV infection has progressed considerably as a result of the implementation of interferon‐free, direct‐acting antiviral (DAA)‐based combination therapies, the resistance of HCV to DAAs has played an important role in the failure of interferon‐free treatment regimens . Moreover, those fortunate enough to be cured of chronic hepatitis C with DAAs may remain at risk for liver cancer for an indefinite period . Consequently, the prevention of liver cancer due to hepatitis C should involve at least three aspects: (a) preventing widespread transmission of HCV among the general population, (b) continuously investing in the development of the HCV vaccine, and (c) strengthening programs for weight management and increasing the rate of antiviral treatment for HCV as these drugs become less expensive to procure.…”

Section: Discussionmentioning

confidence: 99%

“…37 Moreover, those fortunate enough to be cured of chronic hepatitis C with DAAs may remain at risk for liver cancer for an indefinite period. 38,39 Consequently, the prevention of liver cancer due to hepatitis C should involve at least three aspects: (a) preventing widespread transmission of HCV among the general population, (b) continuously investing in the development of the HCV vaccine, and (c) strengthening programs for weight management and increasing the rate of antiviral treatment for HCV as these drugs become less expensive to procure. Alcohol use and NASH are widely known risk factors for the development of liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China

et al. 2019

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Background Liver cancer is a commonly diagnosed malignancy in China. The etiologies of liver cancer are widely known, although studies on temporal trends in liver cancer caused by specific etiologies are rare. Methods Data on the incidence and mortality of liver cancer were retrieved from the Global Burden of Diseases Study 2017. The estimated annual percentage change (EAPC) was used to quantify temporal trends in the age‐standardized incidence rate (ASIR) and the age‐standardized mortality rate (ASMR) of liver cancer from 1990 to 2017. Results Nationwide, the number of incident cases of liver cancer increased from 258 000 in 1990 to 515 900 in 2017. The ASIR decreased from 27.16 per 100 000 to 26.04 per 100 000 during this period, with an EAPC of −0.64 (95% confidence interval [CI] −0.84, −0.44). The number of deaths increased from 245 300 in 1990 to 418 200 in 2017, and the ASMR decreased from 26.72 to 21.30 (EAPC = −1.16, 95% CI −1.35, −0.97). The most pronounced decreases in the ASIR and ASMR were observed in liver cancer due to hepatitis B and in people aged 15‐49 years. Conclusions Since the extensive efforts for prevention of hepatitis B virus infection, the incidence of liver cancer due to hepatitis B has significantly decreased. However, liver cancer due to hepatitis C, NASH, and other causes remains a major public health concern. Additional preventive strategies tailored to liver cancer are needed to further reduce its disease burden in China.

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“…The latter observation has led to clinical proof-of-concept studies of an antagomir as an antiviral agent against hepatitis C [35,36]. Exciting discoveries continue to be generated, including the identification of additional layers of information within the genomic RNA (''codes within the code") [37], mechanisms regulating the turnover of viral RNA and its interactions with host proteins and microRNAs [38], and the discovery of HCV RNA as a 'microRNA sponge', with potential implications for the pathogenesis of hepatitis C and of HCV-related hepatocellular carcinoma (HCC) [39].…”

Section: Hcv Rnamentioning

confidence: 99%

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Moradpour

Grakoui

Manns

2016

Journal of Hepatology

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With the latest all-oral interferon- and ribavirin-free regimens based on direct acting antivirals against the hepatitis C virus (HCV), sustained virological response rates of >90% are achieved, which is equivalent to cure. This has become possible for all genotypes and all subgroups of patients, including many of the most difficult-to-treat populations so far. Since a prophylactic HCV vaccine is not yet available, control of HCV infection will for the time being have to rely on the use of effective and safe antiviral treatments as well as their accessibility and affordability. Different approaches may apply to different parts of the world, eradication of HCV representing a major long-term goal. Whether hepatitis C becomes the first chronic viral infection to be eradicated without a prophylactic vaccine remains to be shown. Here, we briefly summarize advances in the molecular virology of hepatitis C, highlight lessons of biological relevance that were learned through the study of HCV, and its translational and clinical implications. We have also listed selected unsolved challenges, emphasizing that HCV is a unique model and that advances in this direction may yield knowledge of broad biological significance, novel technologies and insights into related important human pathogens.

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The yin and yang of hepatitis C: synthesis and decay of hepatitis C virus RNA

Cited by 35 publications

References 154 publications

Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies

Viral genome imaging of hepatitis C virus to probe heterogeneous viral infection and responses to antiviral therapies

Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

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