Nuclear localization of the C1 factor (host cell factor) in sensory neurons correlates with reactivation of herpes simplex virus from latency

Abstract

After a primary infection, herpes simplex virus is maintained in a latent state in neurons of sensory ganglia until complex stimuli reactivate viral lytic replication. Although the mechanisms governing reactivation from the latent state remain unknown, the regulated expression of the viral immediate early genes represents a critical point in this process. These genes are controlled by transcription enhancer complexes whose assembly requires and is coordinated by the cellular C1 factor (host cell factor). In contrast to other tissues, the C1 factor is not detected in the nuclei of sensory neurons. Experimental conditions that induce the reactivation of herpes simplex virus in mouse model systems result in rapid nuclear localization of the protein, indicating that the C1 factor is sequestered in these cells until reactivation signals induce a redistribution of the protein. The regulated localization suggests that C1 is a critical switch determinant of the viral lytic-latent cycle.

Combinatorial Transcription of Herpes Simplex Virus and Varicella Zoster Virus Immediate Early Genes Is Strictly Determined by the Cellular Coactivator HCF-1

“…More significantly, HCF-1 is specifically sequestered in the cytoplasm of sensory neurons, the site of HSV and VZV latency. The data presented here support the model whereby the cytoplasmic localization of HCF-1 would promote the establishment of viral latency and the regulated transport of this coactivator to the nucleus would be a critical stage in the induction of the viral IE genes during the reactivation stage (32).…”

A Protein Sequestering System Reveals Control of Cellular Programs by the Transcriptional Coactivator HCF-1

“…This localization has been hypothesized to regulate the transcriptional functions of HCF-1 and to be a major controlling determinant in the establishment of and reactivation from the latent state for herpes simplex virus (30). The phenomenon provided a concept for the development of an inducible cytoplasmic sequestering system for the analysis of the cellular functions of HCF-1.…”

“…This approach is reflective of the specific cytoplasmic sequestering of HCF-1 in sensory neurons, the single exception to the nuclear localization pattern of the protein in most cell types (30). This system produces a regulated shift in the nuclear-cytoplasmic ratio of HCF-1, exhibits low toxicity, and allows for the delineation of events that are critically dependent upon the levels of nuclear HCF-1.…”

“…Most notably, in sensory neurons, HCF-1 is normally sequestered in the cytoplasm and is translocated to the nucleus upon various stress stimuli that initiate the reactivation of HSV from the latent state in these cells. This reactivation model proposes that transport of HCF-1 is important for the direct induction of HSV IE genes by assembly of VP16-independent transcriptional complexes during the initial reactivation process (30). However, HCF-1 may also be important in an indirect manner by stimulation of the expression of activators (i.e.…”

Transcriptional coactivator HCF-1 couples the histone chaperone Asf1b to HSV-1 DNA replication components

“…The protein is sequestered in the cytoplasm of unstimulated sensory neurons where these viruses establish latency. Upon stimulation, HCF-1 is rapidly transported to the nucleus and recruited to the viral IE promoters during the initiation of viral reactivation (12)(13)(14). As repressive and activating chromatin modifications correlate with latency and reactivation, respectively (15)(16)(17)(18)(19)(20), it has been hypothesized that HCF-1 modification complexes may play a central role in this process, in a manner analogous to its role in the initiation of viral lytic infection.…”