Article

Transient Activation of the PI3K-AKT Pathway by HCV to Enhance Viral Entry.

University of Southern California, United States
Journal of Biological Chemistry (Impact Factor: 4.6). 10/2012; DOI: 10.1074/jbc.M112.414789
Source: PubMed

ABSTRACT The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Here we report that HCV transiently activates the PI3K-AKT pathway. This activation was observed as early as 15 minutes post-infection, peaked by 30 minutes, and became undetectable at 24 hours post-infection. The activation of AKT could also be mediated by UV-inactivated HCV, HCV pseudoparticle (HCVpp) and the ectodomain of the HCV E2 envelope protein. Since antibodies directed against CD81 and claudin-1, but not antibodies directed against SR-BI or occludin, could also activate AKT, the interaction between HCV E2 and its two co-receptors CD81 and claudin-1 likely triggered the activation of AKT. This activation of AKT by HCV was important for HCV infectivity, as the silencing of AKT by siRNA or the treatment of cells with its inhibitors or with the inhibitor of its upstream regulator PI3K significantly inhibited HCV infection, whereas the expression of constitutively active AKT enhanced HCV infection. The PI3K-AKT pathway is likely involved in HCV entry, as the inhibition of this pathway could inhibit the entry of HCVpp but not the VSV pseudoparticle (VSVpp) into cells. Furthermore, the treatment of cells with the AKT inhibitor AKT-V prior to HCV infection inhibited HCV infection whereas the treatment after HCV infection had no obvious effect. Taken together, our studies indicated that HCV transiently activates the PI3K-AKT pathway to facilitate its entry. These results provide important information for understanding HCV replication and pathogenesis and raised the possibility of targeting this cellular pathway to treat HCV patients.

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