Towards a mechanistic model of herpes simplex virus primary envelopment mediated by the nuclear egress complex

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Herpesviruses cause lifelong latent infections in a wide range of vertebrates including humans. Reactivation of a latent infection leads to a single or multiple rounds of disease and enables new infections. At the center of reactivation is viral egress a process of assembly and release of multiple progeny virions from an infected cell. This complex process involves a range of specific protein-protein interactions among multiple viral and host proteins. Some key features of viral egress have been elucidated; however, a detailed mechanistic understanding of the process is still missing. This proposal focuses on nuclear egress, which involves envelopment of viral capsids at the inner nuclear membrane (INM) and the subsequent de-envelopment at the outer nuclear membrane (ONM). As a result, the capsids get relocated from the nucleus to the cytoplasm where final envelopment takes place at Trans-Golgi-Network-derived vesicles. Two conserved herpesvirus proteins are essential for nuclear egress and form the nuclear egress complex (NEC). The NEC enables the primary envelopment of viral capsids at the inner nuclear membrane by a yet unknown mechanism. This step in viral egress is conserved among all herpesvirus subfamilies and is required for viral replication. In herpes simplex viruses (HSVs), the NEC consists of proteins UL31 and UL34.Here, I propose to biochemically, biophysically and structurally characterize the HSV proteins UL31 and UL34 and their complex, the NEC, with the goal of determining the molecular mechanism of primary capsid envelopment. The interaction of UL31 with UL34, as well as the proposed ability of membrane deformation by this complex requires further analysis as it is a key feature in nuclear egress of all herpesviruses. To date, only very limited biochemical data and no detailed structural information is available on UL31 and UL34. As a result, the detailed mechanism by which these two proteins enable capsid envelopment remains unknown. The proposed research aims to understand the structural aspects and molecular mechanism of nuclear egress of herpesviruses in more detail. A precise understanding of this process should aid the development of antiviral therapeutics that hinder egress and thus viral reactivation.