Abstract
Interferon-induced BST2/Tetherin prevents budding of vpu-deficient HIV-1 by tethering mature viral particles to the plasma membrane. BST2 also inhibits release of other enveloped viruses including Ebola virus and Kaposi's sarcoma associated herpesvirus (KSHV), indicating that BST2 is a broadly acting antiviral host protein. Unexpectedly however, recovery of human cytomegalovirus (HCMV) from supernatants of BST2-expressing human fibroblasts was increased rather than decreased. Furthermore, BST2 seemed to enhance viral entry into cells since more virion proteins were released into BST2-expressing cells and subsequent viral gene expression was elevated. A significant increase in viral entry was also observed upon induction of endogenous BST2 during differentiation of the pro-monocytic cell line THP-1. Moreover, treatment of primary human monocytes with siRNA to BST2 reduced HCMV infection, suggesting that BST2 facilitates entry of HCMV into cells expressing high levels of BST2 either constitutively or in response to exogenous stimuli. Since BST2 is present in HCMV particles we propose that HCMV entry is enhanced via a reverse-tethering mechanism with BST2 in the viral envelope interacting with BST2 in the target cell membrane. Our data suggest that HCMV not only counteracts the well-established function of BST2 as inhibitor of viral egress but also employs this anti-viral protein to gain entry into BST2-expressing hematopoietic cells, a process that might play a role in hematogenous dissemination of HCMV.
Highlights
Human cytomegalovirus (HCMV), a b-herpesvirus, maintains a lifelong, asymptomatic infection in immunocompetent hosts but is an opportunistic pathogen in immunocompromised individuals [1,2]
Since BST2 is present in HCMV particles we propose that HCMV entry is enhanced via a reverse-tethering mechanism with BST2 in the viral envelope interacting with BST2 in the target cell membrane
BST2 has been shown to prevent the release of many different viruses, including the human immunodeficiency virus and Ebola virus, from infected cells by tethering the viral envelope to the host cell membrane
Summary
Human cytomegalovirus (HCMV), a b-herpesvirus, maintains a lifelong, asymptomatic infection in immunocompetent hosts but is an opportunistic pathogen in immunocompromised individuals [1,2]. HCMV is the leading infectious cause of congenital birth defects in neonates [3]. In post-transplant patients HCMV is capable of causing disseminated disease in most organs and tissue types [4,5,6]. HCMV is able to infect a wide range of host cells. The host factors required for viral entry into different cell types are incompletely understood. The two known pathways of HCMV entry are fusion with the plasma membrane and endocytosis. The respective pathway used is dependent on the cell type and viral glycoprotein composition [8,9]. The role of cellular receptors in each of these processes is largely unknown, and it is likely that yet to be identified cellular proteins will be involved in viral entry processes
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