The inhibition of type I interferon signaling by herpes simplex virus 1
By: by Karen Elizabeth Johnson
Published: 2009
Language: eng
Number of pages: 157
Description: Viruses and their hosts are involved in an ongoing arms race, whereby host cells must protect themselves to survive and viruses must get past host defenses to successfully replicate. Type I interferon (IFNα/β) is an important non-specific antiviral cytokine that is induced by viral infection in many cell types. Pretreatment of cells with interferon inhibits replication of a number of viruses, including herpes simplex virus 1 (HSV-1). HSV-1 has evolved several mechanisms that antagonize type I IFN signaling. The HSV-1 ICP27 protein is necessary and sufficient to inhibit IFNαa-induced Stat-1 phosphorylation and nuclear accumulation. However, ICP27 is not necessary to inhibit interferon stimulated gene 15 (ISG15) expression, arguing that HSV-1 encodes at least two mechanisms of inhibition of the IFNα signaling pathway. Types I and II IFN signaling share Jak-1 and Stat-1 in their respective pathways, and though type I IFN signaling is inhibited by HSV-1, type II signaling is not. There is also ICP27-dependent inhibition of Jak-1 activation but no induction of the Jak-1 inhibitor, SOCS3. Though the IFNα receptor subunits IFNAR1 and IFNAR2 are stable during HSV-1 infection, there is internalization of IFNAR1 in some cells. These data suggest that ICP27-dependent inhibtion of IFNα signaling occurs at or before Jak-1 activation.

Finally, HSV-1 infection and ICP27 expression alone stimulate the secretion of an IFNα-antagonizing factor. Preliminary characterization of this factor showed that it is heat-stable, protease-sensitive, and between 10-50 kDa. Because of the previously described roles of ICP27 in RNA processing, we hypothesized that this factor might be the secreted splice variant of IFNAR2. However, HSV-1 does not appear to alter the splicing or nuclear export of IFNAR2 mRNAs. Our data are consistent with at least two models of inhibition of IFNα-induced Stat-1 phosphorylation by HSV-1. The first is that ICP27 causes the internalization of the IFNα receptors, desensitizing cells to the effects of IFN treatment. The second is that ICP27 causes the secretion of a factor that competes for binding between IFNα and IFNAR. These studies have important implications for viral spread and may lead to the production of more effective vaccines and antiviral treatments.
Notes: "April 2009."

Thesis (Ph.D., Division of Medical Sciences (Virology))--Harvard University, 2009.

Includes bibliographical references.