Combating Hepatitis C Virus by Targeting MicroRNA-122 Using Locked Nucleic Acids

Machlin, Erica S.; Sarnow, Peter; Sagan, Selena M.

doi:10.2174/156652312802083558

Cited by 21 publications

(13 citation statements)

References 47 publications

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“…Briefly, control or Xrn2 siRNAs were transfected into Huh7 cells, which were infected with HCV one day later. Modified locked nucleic acids (LNAs) with base complementarity to miR-122 or control miR-106b (Elmen et al, 2008; Machlin et al, 2012) were transfected one day after infection with HCV. RNA samples were prepared and analyzed in Northern blots (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Hepatitis C Virus Subverts Liver-Specific miR-122 to Protect the Viral Genome from Exoribonuclease Xrn2

Sedano

Sarnow

2014

Cell Host & Microbe

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Summary The abundant, liver-specific, microRNA miR-122 forms extensive base-pairing interactions with the 5’ noncoding region of the hepatitis C virus (HCV) RNA genome, protecting the viral RNA from degradation. We discovered that the 5’-3’ exoribonuclease Xrn2, which plays a crucial role in the transcription termination of RNA polymerase II, modulates HCV RNA abundance in the cytoplasm but is counteracted by miR-122-mediated protection. Specifically, Xrn2 depletion results in increased accumulation of viral RNA, while Xrn2 overexpression diminishes viral RNA abundance. Depletion of Xrn2 did not alter translation or replication rates of HCV RNA, but affected viral RNA stability. Importantly, during sequestration of miR-122, Xrn2 depletion restored HCV RNA abundance, arguing that Xrn2 depletion eliminates the miR-122 requirement for viral RNA stability. Thus, Xrn2 has a cytoplasmic, antiviral function against HCV that is counteracted by HCV subversion of miR-122 to form a protective oligomeric complex at the 5’ end of the viral genome.

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Section: Resultsmentioning

confidence: 99%

Hepatitis C Virus Subverts Liver-Specific miR-122 to Protect the Viral Genome from Exoribonuclease Xrn2

Sedano

Sarnow

2014

Cell Host & Microbe

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110

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“…In particular, miR-122, a liver-specific miR, has been shown to dramatically facilitate the efficient replication of HCV RNA by regulating lipid metabolism or the stress response (Baek et al, 2014). Combating HCV by targeting miR-122 has recently been the focus of a clinical trial (Machlin et al, 2012) likely to contribute to the HCV life cycle. In 2013, Shrivastava et al summarized the altered expression of miRs in association with HCV infection and liver disease progression (Shrivastava et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of microRNA-199a-5p reduces the replication of HCV via regulating the pro-survival pathway

et al. 2015

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“…Micro-RNAs (miRs) are increasingly under investigation as both targets for direct antiviral agents against the hepatitis C virus (HCV) [Jopling et al, 2005;Lanford et al, 2010;Machlin et al, 2012;Janssen et al, 2013] and as biomarkers for cancer and acute liver injury [Mitchell et al, 2008;Wang et al, 2009;Okada et al, 2010;Zhang et al, 2010;Bihrer et al, 2011;Antoine et al, 2013]. They are highly conserved, small, single stranded RNA molecules of either human or viral origin, and are created in the nucleus for future regulation of messenger RNAs (mRNA) [Kim, 2005;Grassmann and Jeang, 2008;Kumar, 2011].…”

Section: Introductionmentioning

confidence: 99%

Micro-RNA-122 levels in acute liver failure and chronic hepatitis C

et al. 2014

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MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV–HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P<0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P<0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed.

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Combating Hepatitis C Virus by Targeting MicroRNA-122 Using Locked Nucleic Acids

Cited by 21 publications

References 47 publications

Hepatitis C Virus Subverts Liver-Specific miR-122 to Protect the Viral Genome from Exoribonuclease Xrn2

Hepatitis C Virus Subverts Liver-Specific miR-122 to Protect the Viral Genome from Exoribonuclease Xrn2

Inhibition of microRNA-199a-5p reduces the replication of HCV via regulating the pro-survival pathway

Micro-RNA-122 levels in acute liver failure and chronic hepatitis C

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