Intrinsic immune mechanisms constitute an antiviral frontline defense mediated by constitutively expressed proteins termed “restriction factors”. Human Cytomegalovirus (HCMV) has evolved mechanisms to efficiently evade the antiviral state. We have demonstrated that the DNA sensor IFI16 restricts HCMV replication by down-regulating viral early and late mRNAs as well as their protein expression. Here, we show that during early stages of infection, HCMV induces IFI16 overexpression in primary human fibroblasts (HELF). Despite this induction, continuous virus replication indicates that somehow the virus is able to escape IFI16 restriction activity. Confocal microscopy revealed that, starting from 24 hours post infection, IFI16 relocalizes from the nucleus to the virus assembly complex (AC), where it colocalizes with viral structural proteins such as gB and pp65. We demonstrate that the viral kinase pUL97 binds and phosphorylates IFI16 thus triggering its egression from the nucleus of infected cells. Then, the IFI16-AC complex allows IFI16 carriage in the newly assembled virions where it is embedded in the matrix superficial layers as demonstrated by electron microscopy analysis. Altogether, these data shows a new mechanism through which HCMV is able to neutralize IFI16 restriction activity by inducing first its delocalization and then its trapping into egressing virions.

A NOVEL MECHANISM OF HUMAN CYTOMEGALOVIRUS EVASION FROM RESTRICTION FACTOR IFI16.

DELL'OSTE, Valentina;GATTI, DEBORAH;GUGLIESI, Francesca;DE ANDREA, Marco;BIOLATTI, Matteo;
2013

Abstract

Intrinsic immune mechanisms constitute an antiviral frontline defense mediated by constitutively expressed proteins termed “restriction factors”. Human Cytomegalovirus (HCMV) has evolved mechanisms to efficiently evade the antiviral state. We have demonstrated that the DNA sensor IFI16 restricts HCMV replication by down-regulating viral early and late mRNAs as well as their protein expression. Here, we show that during early stages of infection, HCMV induces IFI16 overexpression in primary human fibroblasts (HELF). Despite this induction, continuous virus replication indicates that somehow the virus is able to escape IFI16 restriction activity. Confocal microscopy revealed that, starting from 24 hours post infection, IFI16 relocalizes from the nucleus to the virus assembly complex (AC), where it colocalizes with viral structural proteins such as gB and pp65. We demonstrate that the viral kinase pUL97 binds and phosphorylates IFI16 thus triggering its egression from the nucleus of infected cells. Then, the IFI16-AC complex allows IFI16 carriage in the newly assembled virions where it is embedded in the matrix superficial layers as demonstrated by electron microscopy analysis. Altogether, these data shows a new mechanism through which HCMV is able to neutralize IFI16 restriction activity by inducing first its delocalization and then its trapping into egressing virions.
5th European Congress of Virology
Lyon (France)
11-14/09/2013
Virologie
84
84
http://www.eurovirology2013.eu
V. Dell’Oste; D. Gatti; F. Gugliesi; M. De Andrea; M. Biolatti; M. Vallino; M. Marschall; M. Gariglio; S. Landolfo.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/138199
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