Herpesviruses replicate and package their genomes in the cell nucleus. In order to begin its process of escape from the cell, the virus must pass through the nuclear membrane by first budding into the inner nuclear membrane in a process called primary envelopment. The mechanism of herpesvirus envelopment is significant to human health from two points of view. First, this process represents an attractive target for therapy in that it is dissimilar in many ways to any normal cellular process, essential to the virus, and common to all herpesviruses. Second, the envelopment machinery alters the organization of the nuclear envelope and provides a useful tool for studying that organization. The research proposed here builds on our studies of herpes simplex virus UL34, an essential component of the envelopment apparatus. Results from our initial period of funding suggest that this protein plays critical roles in at least three aspects of envelopment including (i) recruitment of viral proteins to the nuclear envelope, (ii) dispersal of nuclear envelope components that prevent access of the capsid to the nuclear membrane, and (iii) wrapping of the nucleocapsid in the nuclear membrane. The specific goals of the proposed research are threefold 1. We will define essential functions of the UL34 protein by characterizing a set of seven non-functional mutant UL34 proteins already in hand, and others that we will generate by mutagenesis of conserved residues, for their ability to perform various functions required for envelopment. 2. We will characterize critical interactions between the UL34 protein and other viral proteins involved in envelopment. This will include experiments to test the hypothesis that UL34 mediates membrane wrapping of the capsid, and a screen for interactions of UL34 with other viral proteins that may participate in envelopment. 3. We will fully characterize changes in the host cell nuclear lamina associated with infection and determine the mechanism by which UL34 and other viral proteins accomplish those changes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI041478-06A2
Application #
7033381
Study Section
Virology - B Study Section (VIRB)
Program Officer
Beisel, Christopher E
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$258,125
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Vu, Amber; Poyzer, Chelsea; Roller, Richard (2016) Extragenic Suppression of a Mutation in Herpes Simplex Virus 1 UL34 That Affects Lamina Disruption and Nuclear Egress. J Virol 90:10738-10751
Chuluunbaatar, Uyanga; Roller, Richard; Mohr, Ian (2012) Suppression of extracellular signal-regulated kinase activity in herpes simplex virus 1-infected cells by the Us3 protein kinase. J Virol 86:7771-6
Roller, Richard J; Haugo, Alison C; Kopping, Nora J (2011) Intragenic and extragenic suppression of a mutation in herpes simplex virus 1 UL34 that affects both nuclear envelope targeting and membrane budding. J Virol 85:11615-25
Haugo, Alison C; Szpara, Moriah L; Parsons, Lance et al. (2011) Herpes simplex virus 1 pUL34 plays a critical role in cell-to-cell spread of virus in addition to its role in virus replication. J Virol 85:7203-15
Chuluunbaatar, Uyanga; Roller, Richard; Feldman, Morris E et al. (2010) Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication. Genes Dev 24:2627-39
Leach, Natalie R; Roller, Richard J (2010) Significance of host cell kinases in herpes simplex virus type 1 egress and lamin-associated protein disassembly from the nuclear lamina. Virology 406:127-37
Roller, Richard J; Bjerke, Susan L; Haugo, Alison C et al. (2010) Analysis of a charge cluster mutation of herpes simplex virus type 1 UL34 and its extragenic suppressor suggests a novel interaction between pUL34 and pUL31 that is necessary for membrane curvature around capsids. J Virol 84:3921-34
Wisner, Todd W; Wright, Catherine C; Kato, Akihisa et al. (2009) Herpesvirus gB-induced fusion between the virion envelope and outer nuclear membrane during virus egress is regulated by the viral US3 kinase. J Virol 83:3115-26
Roller, R J; Zhou, Y; Schnetzer, R et al. (2000) Herpes simplex virus type 1 U(L)34 gene product is required for viral envelopment. J Virol 74:117-29