Herpes simplex virus (HSV) causes lifelong latent infections in humans. It is responsible for significant disease, ranging from cold sores and genital infections to blindness and fatal encephalitis. The long- term goal of this project is to understand the molecular mechanisms that HSV uses to gain entry into host cells. An emerging concept in herpesvirology is that endosomal pH of the host cell is required for viral entry, often in a cell type specific manner. However, the mechanistic role that low pH plays in herpes viral entry is not clear. HSV utilizes a low pH, endocytic pathway for infection of epithelial cells, the primary portal of entry into the human host and the site of recurrent infection. HSV gB belongs to the class III viral fusion protein family, whose members also drive the entry several other important enveloped viruses. The class III fusion mechanism remains poorly defined. The focus of this proposal is the delineation of the mechanism of low pH membrane fusion mediated by HSV. Based on previous results and our new preliminary studies, we have formulated three specific aims.
In Specific Aim # 1, we will elucidate viral and cellular parameters of HSV membrane fusion triggered by low pH. We will reveal critical regions of the fusion protein gB and define the roles of cellular receptors in cell-cell fusion triggered by low pH.
In Aim 2, we will delineate a novel role for an HSV envelope protein, not previously associated with fusion and entry. We will elucidate its importance for conformational changes triggered by acidic pH.
For Aim 3, we will determine the functional consequences of the interaction between HSV gH/gL and gB in the context of low pH fusion and entry. Our experimental design employs techniques of molecular virology, biochemistry and cell biology. Achieving these aims will fill critical knowledge gaps about how the complex fusion mechanism of herpesviruses is triggered by host intravesicular pH in physiologically relevant cell types. The results will represent significant advances in our understanding of class III fusion mechanisms, and may aid in development of novel, antiviral interventions.

Public Health Relevance

Herpes simplex viruses cause cold sores and sexually transmitted infections, and can also cause the serious complications of neonatal infections, blindness, and fatal encephalitis. The purpose of this research is to determine how proteins on the surface of herpes simplex virus initiate infection in humans by studying the interaction of virus and virus components with host cells. Greater understanding of the virus entry process will help to identify novel approaches to prevent herpes infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI119159-05
Application #
9677115
Study Section
Virology - A Study Section (VIRA)
Program Officer
Beisel, Christopher E
Project Start
2015-05-15
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Weed, Darin J; Dollery, Stephen J; Komala Sari, Tri et al. (2018) Acidic pH Mediates Changes in Antigenic and Oligomeric Conformation of Herpes Simplex Virus gB and Is a Determinant of Cell-Specific Entry. J Virol 92:
Pastenkos, Gabrielle; Lee, Becky; Pritchard, Suzanne M et al. (2018) Bovine Herpesvirus 1 Entry by a Low-pH Endosomal Pathway. J Virol 92:
Weed, Darin J; Nicola, Anthony V (2017) Herpes simplex virus Membrane Fusion. Adv Anat Embryol Cell Biol 223:29-47
Wudiri, George A; Nicola, Anthony V (2017) Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1. J Virol 91:
AlHajri, Salim M; Cunha, Cristina W; Nicola, Anthony V et al. (2017) Ovine Herpesvirus 2 Glycoproteins B, H, and L Are Sufficient for, and Viral Glycoprotein Ov8 Can Enhance, Cell-Cell Membrane Fusion. J Virol 91:
Weed, Darin J; Pritchard, Suzanne M; Gonzalez, Floricel et al. (2017) Mildly Acidic pH Triggers an Irreversible Conformational Change in the Fusion Domain of Herpes Simplex Virus 1 Glycoprotein B and Inactivation of Viral Entry. J Virol 91:
Wudiri, George A; Schneider, Seth M; Nicola, Anthony V (2017) Herpes Simplex Virus 1 Envelope Cholesterol Facilitates Membrane Fusion. Front Microbiol 8:2383
Nicola, Anthony V (2016) Herpesvirus Entry into Host Cells Mediated by Endosomal Low pH. Traffic 17:965-75
Stone, Jacquelyn A; Nicola, Anthony V; Baum, Linda G et al. (2016) Multiple Novel Functions of Henipavirus O-glycans: The First O-glycan Functions Identified in the Paramyxovirus Family. PLoS Pathog 12:e1005445
Arnatt, Christopher K; Falls, Bethany A; Yuan, Yunyun et al. (2016) Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. Bioorg Med Chem 24:5969-5987

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