Mechanisms of HSV egress

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Herpes simplex virus 1 (HSV-1) is a human pathogen which infects the epithelial cells of the mucosal tissues where the virus undergoes entry, replication, assembly and egress, leading to productive infection. Following primary replication, the virus invades the sensory neurons to establish latency. Reactivation from latency occurs periodically, which is a lifelong source of virus responsible for recurrent infections. As a large DNA virus, HSV-1 assembles progeny capsids in the nucleus of infected cells. To exit, HSV-1 traverses the nucleoplasm, crosses the lamina of a dense meshwork of lamin filaments, and buds through the nuclear membranes in a two-step process known as “envelopment and de-envelopment”. Therefore, the virus drives vesiculation of the inner nuclear membrane and forms enveloped virions in the perinuclear space. Primary virions then fuse with the outer nuclear membrane to release the naked capsids for further maturation. In this process the nuclear egress complex, composed of viral proteins UL31 and UL34, plays an essential role. While UL31/UL34 orchestrates a series of events, the regulatory circuit is unclear in virus-infected cells. Accumulating evidence suggests the hypothesis that additional virus and host factors may work coordinately, which is particularly relevant to temporal or cell-type specific regulation of viral replication. This research will investigate the mechanism of HSV nuclear egress, with a focus on a virulence factor γ134.5. Firstly, genetic analysis will be performed to identify viral determinants that direct host p32/gC1qR and protein kinase C to the sites of nuclear budding. Furthermore, studies will be carried out to examine the nature of host factor recruitment. Secondly, systematic analysis will be integrated to investigate the interplay of 134.5 and the nuclear egress complex. The objective is to define the pathways that control local dissolution of nuclear lamina and capsid transit in the nucleoplasm upon virus infection. Together, these studies will provide insights into the remodeling of nuclear envelope pertinent to herpesvirus replication and maturation.