Abstract
BackgroundDespite the development and availability of hepatitis A virus (HAV) vaccine, HAV infection is still a major cause of acute hepatitis that occasionally leads to fatal liver disease. HAV internal ribosomal entry-site (IRES) is one of the attractive targets of antiviral agents against HAV. The aim of the present study is to evaluate the impact of La, one of the cellular proteins, on HAV IRES-mediated translation and HAV replication.Methods and FindingsWe investigated the therapeutic feasibility of siRNAs specific for cellular cofactors for HAV IRES-mediated translation in cell culture. It was revealed that siRNA against La could inhibit HAV IRES activities as well as HAV subgenomic replication. We also found that the Janus kinase (JAK) inhibitors SD-1029 and AG490, which reduce La expression, could inhibit HAV IRES activities as well as HAV replication.ConclusionsInhibition of La by siRNAs and chemical agents could lead to the efficient inhibition of HAV IRES-mediated translation and HAV replication in cell culture models. La might play important roles in HAV replication and is being exploited as one of the therapeutic targets of host-targeting antivirals.
Highlights
Hepatitis A virus (HAV) is a non-enveloped single-stranded RNA virus, with,7.6 kb positive-sense genome
Inhibition of La by siRNAs and chemical agents could lead to the efficient inhibition of hepatitis A virus (HAV) internal ribosomal entry-site (IRES)-mediated translation and HAV replication in cell culture models
polyadenylate-binding protein-1 (PABP), eukaryotic translation initiation factor 4E (eIF4E) and eIF4G interact with HAV IRES [33,34,35,36]
Summary
Hepatitis A virus (HAV) is a non-enveloped single-stranded RNA virus, with ,7.6 kb positive-sense genome. HAV genome translation could be initiated by cap-independent mechanism through HAV internal ribosomal entry-site (IRES) with a pyrimidine-rich tract, which is located at the down-stream part of 59NTR [2]. Acute liver failure due to HAV is not common, it is still occasionally fatal [5], despite HAV vaccine having become available [6,7,8]. This emphasizes the importance of the development of antiviral agents against HAV. Despite the development and availability of hepatitis A virus (HAV) vaccine, HAV infection is still a major cause of acute hepatitis that occasionally leads to fatal liver disease. The aim of the present study is to evaluate the impact of La, one of the cellular proteins, on HAV IRES-mediated translation and HAV replication
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