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Novel microRNA-like viral small regulatory RNAs arising during human hepatitis A virus infection

ABSTRACT: MicroRNAs (miRNAs), including host miRNAs and viral miRNAs, play vital roles in regulating host-virus interactions. DNA viruses encode miRNAs that regulate the viral life cycle. However, it is generally believed that cytoplasmic RNA viruses do not encode miRNAs, owing to inaccessible cellular miRNA processing machinery. Here, we provide a comprehensive genome-wide analysis and identification of miRNAs that were derived from hepatitis A virus (HAV; Hu/China/H2/1982), which is a typical cytoplasmic RNA virus. Using deep-sequencing and in silico approaches, we identified 2 novel virally encoded miRNAs, named hav-miR-1-5p and hav-miR-2-5p. Both of the novel virally encoded miRNAs were clearly detected in infected cells. Analysis of Dicer enzyme silencing demonstrated that HAV-derived miRNA biogenesis is Dicer dependent. Furthermore, we confirmed that HAV mature miRNAs were generated from viral miRNA precursors (pre-miRNAs) in host cells. Notably, naturally derived HAV miRNAs were biologically and functionally active and induced post-transcriptional gene silencing (PTGS). Genomic location analysis revealed novel miRNAs located in the coding region of the viral genome. Overall, our results show that HAV naturally generates functional miRNA-like small regulatory RNAs during infection. This is the first report of miRNAs derived from the coding region of genomic RNA of a cytoplasmic RNA virus. These observations demonstrate that a cytoplasmic RNA virus can naturally generate functional miRNAs, as DNA viruses do. These findings also contribute to improved understanding of host-RNA virus interactions mediated by RNA virus-derived miRNAs.

OTHER RELATED OMICS DATASETS IN: PRJNA236334

ORGANISM(S): Homo sapiens Hepatovirus A

PROVIDER: GSE54368 | GEO | 2014/01/24

SECONDARY ACCESSION(S): PRJNA236334

REPOSITORIES: GEO

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Project description:Hepatitis A virus (HAV) is a hepatotropic human picornavirus that has been associated only with acute infection. Its pathogenesis is not well understood since there have been few recent studies in animal models using modern methodologies. We characterized HAV infections in three chimpanzees, quantifying viral RNA by qRT-PCR and examining critical aspects of the innate immune response including intrahepatic interferon-stimulated gene expression. We compared these infection profiles with similar studies of chimpanzees infected with hepatitis C virus (HCV), a hepatotropic flavivirus that frequently causes persistent infection. Surprisingly, HAV-infected animals exhibited very limited induction of type I interferon-stimulated genes in the liver compared to chimpanzees with acute resolving HCV infection, despite similar levels of viremia and 100-fold greater quantities of viral RNA in the liver. Minimal ISG15 and IFIT1 responses peaked 1-2 weeks after HAV challenge, then subsided despite continuing high hepatic viral loads. An acute inflammatory response at 3-4 weeks correlated with the appearance of virus-specific antibodies, and both apoptosis and proliferation of hepatocytes. Despite this, HAV RNA persisted in the liver for months, remaining present long after its clearance from serum and feces and revealing dramatic differences in the kinetics of clearance in the three compartments. Viral RNA was detected in the liver for significantly longer (35 to >48 weeks) than HCV RNA in animals with acute resolving HCV infection (10-20 weeks). Collectively, these findings suggest that early HAV infection is far stealthier than HCV infection and represents a distinctly different paradigm in viral-host interactions within the liver. Chimpanzee liver was biopsied during an acute HAV infection. Chimp 1 and 2 had two baseline samples. Chimp 3 used the baselines from chimps 1 and 2. Chimp 1 had 8 samples during the HAV acute infection. Chimp 2 had 9 samples during the HAV acute infection. Chimp 3 had 4 samples during the HAV acute infection.

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Novel microRNA-like viral small regulatory RNAs arising during human hepatitis A virus infection

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