Abstract
Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5’-untranslated region (5′UTR) and part of the core protein coding sequence, and by the 3′UTR. The 5′UTR has some highly conserved structural regions, while others can assume different conformations. The IRES can bind to the ribosomal 40S subunit with high affinity without any other factors. Nevertheless, IRES activity is modulated by additional cis sequences in the viral genome, including the 3′UTR and the cis-acting replication element (CRE). Canonical translation initiation factors (eIFs) are involved in HCV translation initiation, including eIF3, eIF2, eIF1A, eIF5, and eIF5B. Alternatively, under stress conditions and limited eIF2-Met-tRNAiMet availability, alternative initiation factors such as eIF2D, eIF2A, and eIF5B can substitute for eIF2 to allow HCV translation even when cellular mRNA translation is downregulated. In addition, several IRES trans-acting factors (ITAFs) modulate IRES activity by building large networks of RNA-protein and protein–protein interactions, also connecting 5′- and 3′-ends of the viral RNA. Moreover, some ITAFs can act as RNA chaperones that help to position the viral AUG start codon in the ribosomal 40S subunit entry channel. Finally, the liver-specific microRNA-122 (miR-122) stimulates HCV IRES-dependent translation, most likely by stabilizing a certain structure of the IRES that is required for initiation.
Highlights
Hepatitis C virus (HCV) is an enveloped positive strand RNA virus that preferentially replicates in the liver [1], and it is classified in the genus Hepacivirus in the family Flaviviridae
Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5’-untranslated region (5 UTR) and part of the core protein coding sequence, and by the 3 UTR
IRES activity is modulated by additional cis sequences in the viral genome, including the 3 UTR and the cis-acting replication element (CRE)
Summary
Hepatitis C virus (HCV) is an enveloped positive strand RNA virus that preferentially replicates in the liver [1], and it is classified in the genus Hepacivirus in the family Flaviviridae. Progeny plus strand RNA genomes together with viral proteins are packaged into newly assembled virions [32,47], together with some cellular proteins such as apolipoproteins (Apo) A-I, B, C-II, and E, which contribute to liver tropism of the virus by binding to the infected hepatocytes surface receptors [48]. While the resulting low efficient translation coincides with the “undercover” strategy of HCV replication that often leads to chronic infection and further unnoticed spread of the virus to uninfected individuals, the use of such IRES elements has two more big advantages. MicroRNAs are small single-stranded guide RNAs that direct effector complexes involving Argonaute (Ago) proteins to cellular mRNAs and usually negatively influence the mRNAs translation efficiency and induce degradation of the mRNA [57,58]. Thereby, we touch the functions of miR-122 only with regard to translation regulation, while another review by Joyce Wilson in this review series thoroughly covers miR-122 action in all aspects of HCV replication
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