The neuroinvasive herpesviruses are a highly-prevalent group of the alpha-herpesvirus subfamily that includes the human pathogens: herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and varicella zoster virus (VZV). An additional member of this group is a virus of veterinary significance, pseudorabies virus (PRV), which historically has provided models for studying viral pathogenesis. Despite the availability of the antiviral compound acyclovir, several severe forms of disease caused by these viruses remain prevalent in this country and worldwide. Infections associated with high rates of morbidity or mortality includes encephalitis, keratitis, shingles and disseminated infections in newborns. Novel strategies to interfere with the assembly and egress of these viruses could prove valuable to treatment of infections, yet much of the herpesvirus infectious cycle remains undefined. In this application we leverage our expertise in infectious clone mutagenesis and single viral particle fluorescence imaging methods to dissect viral structural composition in living-cells and extracellularly, and to address the molecular pathways guiding viral assembly and egress. New evidence is provided indicating that the very large herpesvirus tegument protein, VP1/2, is a key effector of viral assembly during distinct stages of assembly in the nucleus and cytoplasm of infected cells. This proposal is based on the hypothesis that herpesvirus assembly and egress are coupled processes that occur through a series of sequential steps both in the nucleus and cytoplasm of infected cells, and that each of these steps are affected in part by the VP1/2 protein. Our goal is to refine our understanding of these steps at the level of the protein interactions that contribute to the dynamics of viral egress. This proposal includes comparative studies of model viruses from the two neuroinvasive herpesviruses subgroups, the simplex viruses (represented by HSV-1) and the varicelloviruses (represented by PRV), to develop a comprehensive analysis of the properties of these viruses.

Public Health Relevance

Neuroinvasive herpesviruses are the causative agents of a number of severe diseases including shingles, encephalitis, neonatal infections and herpes keratitis (the leading cause of infectious blindness in the USA and other industrialized nations). This proposal focuses on understanding the molecular mechanisms that underlie the assembly and egress of herpesvirus particles, with the long- term goal of identifying new targets for the intervention of disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080658-04
Application #
8414430
Study Section
Virology - B Study Section (VIRB)
Program Officer
Challberg, Mark D
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$283,833
Indirect Cost
$97,713
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Maier, Oana; Sollars, Patricia J; Pickard, Gary E et al. (2016) Visualizing Herpesvirus Procapsids in Living Cells. J Virol 90:10182-10192
Bohannon, Kevin Patrick; Jun, Yonggun; Gross, Steven P et al. (2013) Differential protein partitioning within the herpesvirus tegument and envelope underlies a complex and variable virion architecture. Proc Natl Acad Sci U S A 110:E1613-20
Bohannon, Kevin P; Sollars, Patricia J; Pickard, Gary E et al. (2012) Fusion of a fluorescent protein to the pUL25 minor capsid protein of pseudorabies virus allows live-cell capsid imaging with negligible impact on infection. J Gen Virol 93:124-9
Leelawong, Mindy; Lee, Joy I; Smith, Gregory A (2012) Nuclear egress of pseudorabies virus capsids is enhanced by a subspecies of the large tegument protein that is lost upon cytoplasmic maturation. J Virol 86:6303-14
Leelawong, Mindy; Guo, Dongsheng; Smith, Gregory A (2011) A physical link between the pseudorabies virus capsid and the nuclear egress complex. J Virol 85:11675-84