Internal ribosomal entry‐site activities of clinical isolate‐derived hepatitis A virus and inhibitory effects of amantadine

Imazeki, Fumio; Nakamoto, Shingo; Okitsu, Kohichiroh; Fujiwara, Keiichi; Yokosuka, Osamu

doi:10.1111/j.1872-034x.2010.00617.x

Cited by 16 publications

(17 citation statements)

References 34 publications

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“…It is known that the M2 protein of influenza A virus is a target of amantadine [19]. Furthermore, it has been reported to inhibit HAV IRES-mediated translation and replication by our group and other researchers [2,3,5-8]. …”

Section: Short Reportmentioning

confidence: 85%

“…Interestingly, amantadine and IFN also inhibited HAV IRES-mediated translation and HAV replication [2,3,5-8]. Accordingly, we planned to identify more effective strategies for suppressing HAV IRES-mediated translation and HAV replication.…”

Section: Short Reportmentioning

confidence: 99%

“…Therefore, we examined the possibilities of the combination of amantadine and IFN-alpha against HAV because these two drugs were previously reported to be effective against HAV [2,3,5-8]. To our knowledge, this is the first study demonstrating that a combination of amantadine and IFN-alpha can suppress HAV replication more effectively than amantadine or IFN-alpha alone.…”

Section: Short Reportmentioning

confidence: 99%

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Inhibitory effects on HAV IRES-mediated translation and replication by a combination of amantadine and interferon-alpha

Yang

Kiyohara

Imazeki

et al. 2010

Virol J

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Hepatitis A virus (HAV) causes acute hepatitis and sometimes leads to fulminant hepatitis. Amantadine is a tricyclic symmetric amine that inhibits the replication of many DNA and RNA viruses. Amantadine was reported to suppress HAV replication, and the efficacy of amantadine was exhibited in its inhibition of the internal ribosomal entry site (IRES) activities of HAV. Interferon (IFN) also has an antiviral effect through the induction of IFN stimulated genes (ISG) and the degradation of viral RNA. To explore the mechanism of the suppression of HAV replication, we examined the effects of the combination of amantadine and IFN-alpha on HAV IRES-mediated translation, HAV replicon replication in human hepatoma cell lines, and HAV KRM003 genotype IIIB strain replication in African green monkey kidney cell GL37. IFN-alpha seems to have no additive effect on HAV IRES-mediated translation inhibition by amantadine. However, suppressions of HAV replicon and HAV replication were stronger with the combination than with amantadine alone. In conclusion, amantadine, in combination of IFN-alpha, might have a beneficial effect in some patients with acute hepatitis A.

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Section: Short Reportmentioning

confidence: 85%

Section: Short Reportmentioning

confidence: 99%

Section: Short Reportmentioning

confidence: 99%

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Inhibitory effects on HAV IRES-mediated translation and replication by a combination of amantadine and interferon-alpha

Yang

Kiyohara

Imazeki

et al. 2010

Virol J

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“…HAV IRES derived from clinical isolates have shown various activities in in vitro cell culture 5,12. Also complicating this issue is the fact that the definition of acute liver failure differs among different countries 11,14.…”

Section: Introductionmentioning

confidence: 99%

Ultra-Deep Sequencing Analysis of the Hepatitis A Virus 5'-Untranslated Region among Cases of the Same Outbreak from a Single Source

Wu¹,

Nakamoto²,

Jiang³

et al. 2014

Int. J. Med. Sci.

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Hepatitis A virus (HAV) is a causative agent of acute viral hepatitis for which an effective vaccine has been developed. Here we describe ultra-deep pyrosequences (UDPSs) of HAV 5'-untranslated region (5'UTR) among cases of the same outbreak, which arose from a single source, associated with a revolving sushi bar. We determined the reference sequence from HAV-derived clone from an attendant by the Sanger method. Sixteen UDPSs from this outbreak and one from another sporadic case were compared with this reference. Nucleotide errors yielded a UDPS error rate of < 1%. This study confirmed that nucleotide substitutions of this region are transition mutations in outbreak cases, that insertion was observed only in non-severe cases, and that these nucleotide substitutions were different from those of the sporadic case. Analysis of UDPSs detected low-prevalence HAV variations in 5'UTR, but no specific mutations associated with severity in these outbreak cases. To our surprise, HAV strains in this outbreak conserved HAV IRES sequence even if we performed analysis of UDPSs. UDPS analysis of HAV 5'UTR gave us no association between the disease severity of hepatitis A and HAV 5'UTR substitutions. It might be more interesting to perform ultra-deep sequencing of full length HAV genome in order to reveal possible unknown genomic determinants associated with disease severity. Further studies will be needed.

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“…The downstream part of 5′NTR represents the internal ribosomal entry site (IRES), which mediates cap-independent translation initiation and is important for HAV replication [9], [10]. 5′NTR of HAV is also known as one of the most highly conserved in the HAV genome sequences, making this region one of the likely candidates for antiviral targets [9], [11]. It was reported that nucleotide variations in the central portion of 5′NTR of HAV may influence the severity of hepatitis A [12].…”

Section: Introductionmentioning

confidence: 99%

Analysis of 5′ Nontranslated Region of Hepatitis A Viral RNA Genotype I from South Korea: Comparison with Disease Severities

et al. 2010

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The aim of the study was to analyze genotype I hepatitis A virus (HAV) 5′ nontranslated region (NTR) sequences from a recent outbreak in South Korea and compare them with reported sequences from Japan. We collected a total of 54 acute hepatitis A patients' sera from HAV genotype I [27 severe disease (prothrombin time INR≥1.50) and 27 mild hepatitis (prothrombin time INR <1.00)], performed nested RT-PCR of 5′ NTR of HAV directly sequenced from PCR products (∼300 bp), and compared them with each other. We could detect HAV 5′NTR sequences in 19 of the 54 (35.1%) cases [12 of 27 severe cases (44.4%) and 7 of 27 self-limited cases (25.9%)], all of which were subgenotype IA. Sequence analysis revealed that sequences of severe disease had 93.6%–99.0% homology and of self-limited disease 94.3%–98.6% homology, compared to subgenotype IA HAV GBM wild-type IA sequence. In this study, confirmation of the 5′NTR sequence differences between severe disease and mild disease was not carried out. Comparison with Japanese HAV A10 revealed 222C to G or T substitution in 8/12 cases of severe disease and 222C to G or T and 392G to A substitutions in 5/7 and 4/7 cases of mild disease, respectively, although the nucleotide sequences in this study showed high homology (93.6%–100%). In conclusion, HAV 5′NTR subgenotype IA from Korea had relatively high homology to Japanese sequences previously reported from Japan, and this region would be considered one of the antiviral targets. Further studies will be needed.

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Internal ribosomal entry‐site activities of clinical isolate‐derived hepatitis A virus and inhibitory effects of amantadine

Abstract: HAV IRES derived from clinical isolates have various activities. Bicistronic reporter assay using clinical isolates may be another useful tool for testing antiviral activities like those of amantadine and the new acridines and hydrazones recently reported.

Cited by 16 publications

References 34 publications

Inhibitory effects on HAV IRES-mediated translation and replication by a combination of amantadine and interferon-alpha

Inhibitory effects on HAV IRES-mediated translation and replication by a combination of amantadine and interferon-alpha

Ultra-Deep Sequencing Analysis of the Hepatitis A Virus 5'-Untranslated Region among Cases of the Same Outbreak from a Single Source

Analysis of 5′ Nontranslated Region of Hepatitis A Viral RNA Genotype I from South Korea: Comparison with Disease Severities

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