FUNCTIONAL ROBES OF HEPATITIS A VIRUS NONSTRUCTURAL PROTEINS IN SIGNAL TRANSDUCTION

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Hepatitis A virus (HAV) infection is still a major problem worldwide. The infection does not induce any visible cytopathic effects, and there is no evidence that HAV interferes with the macromolecular synthesis of its host cells. Recently, in the hepatitis B and C virus infection, intracellular signals have been reported to be induced. To Clarify the effects of HAV infection, we examined the influence of 9 FLAG-HAV (VP2, VP3, VP1-2A, 2B, 2C, 3A, 3BC, 3C, 3D) proteins on various intracellular signaling pathways. Viral protein expression vectors were cotransfacted into HeLa cells with the reporter plasmids, controlled by a synthetic promoter that contains direct 4 repeats of the cyclic AMP response element (CRE), 5 repeats of the serum response factor (SRF), 7 repeats of the activator protein 1 (AP 1), 5 repeats of the nuclear factor kB (NF-kB), and 5 repeats of the serum response element (SRE), respectively. Cells were harvested 42 hours after transfaction, and luciferase assays were performed. Assays were conducted at least in triplicate, and a viral protein activation twice greater than that of the control was defined as significant. HAV FLAG-VP3 protein significantly activated the SRE-associated signal in HeLa cells at a value 2.2± 0.3 times higher than control. However, FLAG-VP3 protein did not activate the CRE-(1.1±0.1), SRF-(1.6± 0.2), AP-1-(1.1±0.1), NF-kB-(0.7±0.1) associated pathways. The other HAV proteins showed no signal activation in the CRE-, SRF-, AP-1-, NF-kB-, and SRE-associated pathways. We found that HAV VP3 protein activated the SRE-associated signal, intracellular signaling pathways associated with cell proliferation, differentiation, in HeLa cells.