BST-2 Expression in Human Hepatocytes is Inducible by All Three Types of Interferons and Restricts Production of Hepatitis C Virus
T. Amet, D. Byrd, N. Hu, Q. Sun, F. Li, Y. Zhao, S. Hu, A. Grantham and Q. Yu
Affiliation: Department of Microbiology and Immunology and Center for AIDS Research, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Bone marrow stromal cell antigen 2 (BST-2, also known as tetherin, CD317, or HM1.24) has
recently been identified as a host restriction factor against diverse families of enveloped viruses. However, the
effects of BST-2 on the life cycle of hepatitis C virus (HCV), an enveloped RNA virus, remain unclear and
controversial. Here we demonstrated that human hepatocytes including Huh7.5.1 cells, primary human
hepatocytes (PHHs), and HepG2 cells constitutively expressed low to moderate levels of endogenous BST-2
on the cell surface, which could be robustly up-regulated by all three types of interferons (IFNs) such as IFN-α,
IFN-γ, and IFN-λ. IFN-α and IFN-γ showed a synergistic effect in induction of BST-2 expression on human
hepatocytes. Over-expression of BST-2 by BST-2-expressing vector transfection or up-regulation of BST-2 by
IFN stimulation markedly suppressed HCV production, whereas shRNA-mediated depletion of endogenous
BST-2 significantly enhanced HCV production in infected Huh7.5.1 cells. IFN-mediated anti-HCV activity was
partially but significantly diminished by shRNA-mediated knockdown of BST-2 expression, indicating that BST-
2 upregulation is directly involved in IFN-mediated inhibition of HCV production. We also found that both BST-2
and HCV core co-localized with intracellular lipid droplets (LDs), suggesting that BST-2-HCV interaction may
take place around LDs as LDs constitute an important intracellular organelle for HCV assembly and replication.
Taken together, our data suggest that BST-2 is a host restriction factor against HCV, and induction of BST-2 in
hepatocytes could be one of the mechanisms by which current HCV standard therapy (IFN-α plus ribavirin)
achieves a sustained virological response (SVR).
Keywords: BST-2, HCV, host restriction factor, Huh7.5.1 cell, interferon, lipid droplet.
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