HMGB1에 의한 C형 간염 바이러스 감염 억제

Abstract

The hepatitis C virus (HCV), which has infected 3% of the world population, leadsto chronic infection and ultimately to liver cirrhosis and hepatocellular carcinoma. Novaccine is available to date and there is no effective therapy for all genotype of HCV.HCV possesses a positive-sense single-stranded RNA with a nucleotide length of 9.6 kb,which encodes a single large precursor polyprotein that is flanked by nontranslatedregions at its 5′ and 3′ ends. The viral polyprotein is processed by cellular and viralproteases into structural and nonstructural proteins. Recently, cell culture systems for invitro infectious-virus production based on the full-length HCV genome of a genotype 2awere established. Replication of HCV RNA occurs around lipid droplets near theendoplasmic reticulum. New virus particles presumably form by budding into theendoplasmic reticulum and leave the cell through the secretary pathway. However, thesites of HCV mRNA translation and genomic RNA encapsidation have not been wellcharacterized. To elucidate this, I investigate subcellular localizations of doublestrandedRNA, newly synthesized RNA, and newly synthesized proteins to identify thetranslation site of HCV mRNAs relative to the replication sites. My results suggest thattranslation of HCV mRNA occurs on newly synthesized RNAs near LDs.Chronic and persistent infection is a characteristic feature of HCV pathogenesis.During chronic infection, production of virus particles is limited, and a restrictednumber of liver cells are infected. These phenomena indicate the existence of balancebetween the HCV infection process and host mechanisms that protect against HCVinfection. High mobility group box 1 (HMGB1), an abundant nuclear protein thattriggers host immune responses, is an endogenous danger signal involved in thepathogeneses of various infectious agents. However, its role in HCV infection is notknown. Here, I report that HMGB1 protein is translocated from the nucleus tocytoplasm, and subsequently released into the extracellular milieu by HCV infection.Secreted HMGB1 triggers anti-viral responses and blocks HCV infection, a mechanismthat may limit HCV propagation in HCV patients. Secreted HMGB1 may also have apotential role in liver cirrhosis, which is a common comorbidity in HCV patients.Further investigations into the roles of HMGB1 in the diseases caused by HCVinfection will shed light on and potentially help prevent these serious and prevalentHCV-related diseases.