Key result
Short-hairpin RNA against La protein successfully suppressed the levels of La protein and hepatitis C virus core protein to 30% of that in control cells.
Why the study?
Does inhibition of La protein repress HCV replication in vitro?
Does inhibition of La protein repress HCV replication in vitro?
Inhibition of La protein substantially represses HCV replication, suggesting it as a potential therapeutic target for Hepatitis C.
La protein inhibition merits further study as HCV target; leaves open clinical translation and safety.
BACKGROUND: Translation of the hepatitis C virus (HCV) is mediated by an internal ribosome entry site (IRES). Here, we analyzed the functional relevance of La protein for replication of HCV using an infectious HCV clone, JFH-1. METHODS: A single-nucleotide mutation from A to U was introduced at the 338th nucleotide in the stem-loop domain IV structure of HCV IRES, which stabilized stem-loop IV and abolished translation and replication of JFH-1 almost completely. RESULTS: During JFH-1 replication, translation initiation factors required for HCV IRES activity, including La protein, polypyrimidine tract binding protein (PTB), PSMA7, and PCBP2, were significantly induced in Huh-7.5 cells. Interestingly, JFH-1 infection increased telomerase activity and induced the expression of human telomerase RNA (hTR) in Huh-7.5 cells. In 37 tissue specimens from patients with chronic hepatitis C, La protein significantly correlated with the representative essential telomerase components hTR, p23, and HSP90 (P<.001). Recombinant adenovirus that expressed short-hairpin RNA against La protein successfully suppressed the levels of La protein and core protein of JFH-1 to 30% of that in the control cells. CONCLUSIONS: HCV infection might be strongly related to telomerase activity in the liver through La protein induction. Inhibition of La protein substantially repressed JFH-1 replication; therefore, La protein is a potential therapeutic target for HCV.
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Shirasaki et al. (2010) studied chronic hepatitis C (n=37). short-hairpin RNA against La protein vs. control cells was evaluated on levels of La protein and core protein of JFH-1. Short-hairpin RNA against La protein successfully suppressed the levels of La protein and hepatitis C virus core protein to 30% of that in control cells.
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