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Role of ICP0 Dimerization in Herpes Simplex Virus Pathogenesis

Award Number: R21AI181336
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Role of ICP0 Dimerization in Herpes Simplex Virus Pathogenesis - PROJECT SUMMARY Herpes simplex virus (HSV) infections can result in life-long oral, ocular, and genital infections that lead to debilitating diseases such as blindness and life-threatening encephalitis. A key aspect of HSV pathogenesis is the ability of the virus to establish a latent infection in sensory neurons, for which repeated reactivations result in viral replication and cellular damage and leads to HSV-mediated diseases. Understanding the components and processes that control latency and reactivation is essential to developing novel and effective therapeutics. A key viral component in controlling the latency-reactivation cycle is the immediate-early protein of HSV known as infected cell protein 0 (ICP0). ICP0 is an E3 ubiquitin (Ub) ligase that significantly enhances the expression of all 3 HSV gene classes required for efficient lytic replication and viral reactivation from latency. Importantly, the transactivation function of ICP0 is linked to dimerization via its C-terminal domain. Genetic studies indicate that ICP0's dimerization/C-terminal domain significantly enhances viral replication and pathogenesis in an animal model of HSV latency and reactivation. Surprisingly, there is very limited information regarding the mechanisms associated with ICP0 protein-protein interaction/dimerization process and function of ICP0. The long-term goal of this proposal is to understand the interactions among and between viral factors and to relate findings from these studies to recurrent herpetic diseases. As an important step in this direction, the X-ray crystal structure of ICP0 dimers has been solved; this structure of ICP0 dimers is a novel fold, as there are no structural homologs in the Protein Data Base. The objective of this application to identify mechanisms by which ICP0 binds to itself to enhance viral transcription. The central hypothesis is that specific C-terminal residues on ICP0 facilitate its dimerization to stimulate its (own) Ub ligase activity, viral gene expression, and productive infection. The rationale for these studies is the concept that structural knowledge of ICP0 and its dimer interface will allow one to understand how this viral protein controls lytic infection and reactivation. To test this hypothesis the following Specific Aims are proposed - Aim 1: Identify ICP0-ICP0 dimerization contacts that stimulate HSV gene expression. Aim 2: Determine the contribution of ICP0 dimerization in HSV-1 replication and pathogenesis. Work from this study is significant and innovative as it will provide the first known molecular structure of a large functional domain for HSV-1 ICP0, uncover at least one mechanism of ICP0 dimer formation, and ascertain how ICP0 self-interactions modulate it key activities and pathogenesis. Results from project can be compared to other herpesviruses that encode orthologs that are functionally similar to ICP0.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $229,624 )
2025	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	2	6/3/2025	NON-COMPETING CONTINUATION	$229,624
														Subtotal = $229,624

Issue Date FY: 2024 ( Subtotal = $200,782 )
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$20,078
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	1	6/26/2024	NEW	$180,704
														Subtotal = $200,782

Grand Total All Awards = $430,406

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Role of ICP0 Dimerization in Herpes Simplex Virus Pathogenesis

Award Number: R21AI181336

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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