Intrinsic immunity is an aspect of
antiviral defense that operates through diverse mechanisms at the intracellular level through a wide range of constitutively expressed cellular
proteins. In the case of herpesviruses, intrinsic resistance involves the repression of viral gene expression during the very early stages of
infection, a process that is normally overcome by viral tegument and/or
immediate-early proteins. Thus, the balance between cellular repressors and virus-counteracting
proteins determines whether or not a cell becomes productively infected. One aspect of intrinsic resistance to herpes simplex virus 1 (HSV-1) is conferred by components of promyelocytic leukemia nuclear bodies (PML NBs), which respond to
infection by accumulating at sites that are closely associated with the incoming parental HSV-1 genomes. Other cellular
proteins, including IFI16, which has been implicated in sensing pathogen
DNA and initiating signaling pathways that lead to an
interferon response, also respond to viral genomes in this manner. Here, studies of the dynamics of the response of PML NB components and IFI16 to invading HSV-1 genomes demonstrated that this response is extremely rapid, occurring within the first hour after addition of the virus, and that human Daxx (hDaxx) and IFI16 respond more rapidly than PML. In the absence of HSV-1 regulatory
protein ICP0, which counteracts the recruitment process, the newly formed, viral-genome-induced PML NB-like foci can fuse with existing PML NBs. These data are consistent with a model involving viral genome sequestration into such structures, thereby contributing to the low probability of initiation of lytic
infection in the absence of ICP0.
IMPORTANCE: Herpesviruses have intimate interactions with their hosts, with
infection leading either to the productive lytic cycle or to a quiescent
infection in which viral gene expression is suppressed while the viral genome is maintained in the host cell nucleus. Whether a cell becomes lytically or quiescently infected can be determined through the competing activities of cellular repressors and viral activators, some of which counteract cell-mediated repression. Therefore, the events that occur within the earliest stages of
infection can be of crucial importance. This paper describes the extremely rapid response to herpes simplex virus 1
infection of cellular
protein IFI16, a sensor of pathogen
DNA, and also of the PML nuclear body
proteins PML and hDaxx, as revealed by live-cell microscopy. The data imply that these
proteins can accumulate on or close to the viral genomes in a sequential manner which may lead to their sequestration and repression.