HSV-1 ICP0-MEDIATED IMPAIRMENT OF HOST INTRINSIC AND INNATE IMMUNE FACTORS

Abstract

Understanding mechanisms viruses use to evade the immune system and to persist within its host, is of crucial relevance in controlling, preventing and treating HSV-1-associated diseases. As reviewed in this dissertation, ICP0 is a key viral regulatory protein that modulates the switch between lytic and latent cycles of the virus. ICP0's role in stimulating viral replication is mediated, in part, by its impairment of the host defenses. The purpose of the current study was to undertake structure/function analyses of ICP0 that will allow us to begin to delineate how ICP0 promotes the dispersion and/or degradation of the antiviral ND10 components and how an established IFN response is disarmed by HSV. From our PML studies, we have defined two overlapping regions within the central N-terminal portion of ICP0 (residues 1 to 311) that promote the dissociation and degradation of PML and dissociation of Sp100 (residues 1 to 427). Additionally we found that the first 388 N-terminal amino acids of ICP0 play a role in impairing the IFN response, with the residues spanning from 212-388 being important for this activity. Overall these N-terminal regions of ICP0 play a vital role in impair two host defenses, ND10 and IFN β. Results from these studies may be used to design therapeutic interventions that limit HSV-1 infections and diseases.