JOHNS HOPKINS UNIVERSITY, THE
?Maturation functions of the HSV-1 tegument?. Herpes simplex virus (HSV) assembles an icosahedral capsid and packages this structure with the viral genome in the nucleus. It then has to exit the nucleus using a complex envelopment/de-envelopment pathway that occurs at the nuclear envelop, translocate the particle to a cytoplasmic site for final envelopment and then make its way to the cell surface. Herpesviruses have also evolved mechanisms that subvert and hijack normal cellular activities to propagate their progeny. Our goal is to understand the mechanism by which the virus acquires its infectious coat and the role of the virus encoded functions in this pathway, primarily by analyzing the functions of two tegument proteins, the UL36 and UL37 gene products. Our central hypothesis is that the UL36 and UL37 gene products specify essential and unique cytoplasmic functions for the maturation of the assembled particle into an infectious virion. Specifically, we propose that UL36 acts to traffic capsids for final envelopment at a cytoplasmic site and that UL37 facilitates exit or initial envelopment at the nuclear membrane and subsequently final envelopment in the cytoplasm by recruiting the Golgi structure or delaying its fragmentation. The goals of this proposal are to understand how these two proteins function in the morphogenesis of the infectious particle, identification of the functional domains required for these activities, the protein-protein interactions that occur during this process and the structural footprints of these proteins in the mature virion. This could potentially lead to the discovery of novel pathways that can be targeted by antiviral intervention. The specific aims to achieve our goals are listed below. Aim 1: Investigating the role of UL36 and UL37 in the maturation of the virus particle using mutant viruses. Aim 2: Protein-protein interactions of UL36 and UL37 with virus and cellular proteins. Aim 3: Structural studies of UL36 and UL37 in capsids and the mature virion. Aim 4: Identification of functional domains of UL36 and UL37.