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Molecular and cellular mechanisms of HSV-1 assembly and egress

Award Number: R01NS117513
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Molecular and cellular mechanisms of HSV-1 assembly and egress - Alpha herpesviruses, including important human pathogen Herpes Simplex Virus 1 (HSV-1) and zoonotic pathogen Pseudorabies Virus (PRV), are among the very few viruses that have evolved to exploit highly-specialized neuronal cell biology. During the natural course of disease, alpha herpesviruses infect sensory and autonomic neurons of the Peripheral Nervous System (PNS). Upon reactivation, progeny virus particles undergo polarized intracellular trafficking and exocytosis at particular sub-cellular sites to spread from cell to cell, which is the subject of this proposal. In PNS neurons, this intracellular trafficking can include sorting into axons for long-distance transport into peripheral tissues, leading to recurrence of herpetic or zosteriform lesions, or to the Central Nervous System (CNS). The human alpha herpesviruses, and HSV-1 in particular, are leading causes of viral encephalitis. In Aim 1, we will investigate the viral factors that our preliminary data suggest modulate intracellular transport in non-neuronal cells, immediately prior to exocytosis, using existing reagents in PRV, and extending to HSV-1. In Aim 2, we will investigate the post-Golgi constitutive secretory pathway mechanisms that direct HSV-1 particle trafficking and exocytosis to particular sub-cellular sites in non- neuronal cells, and which we hypothesize also mediate polarized trafficking and exocytosis in neurons. Using innovative methods to acutely perturb particular cellular factors and directly image virus particle exocytosis, we will determine the role of secretory pathway mechanisms in intracellular trafficking and egress of virus particles, comparing non-neuronal cells to primary PNS neurons. In Aim 3, we will focus on the microtubule motor-based mechanisms that mediate axonal sorting, specifically in PNS neurons. Using a microfluidics-like chambered neuronal culture system and live-cell imaging, we will determine the roles of different kinesin motors and microtubule-associated proteins in axonal sorting of HSV-1 particles. Elucidating the basic cell biological processes that our viruses use in both neurons and non-neuronal cells will increase our understanding of how and why herpesviruses spread to and within the nervous system, lead to the identification of druggable targets and development of better therapies for viral neuropathology, and may provide fundamental insights into cell biology, particularly of the cell biology of neurons.


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: 2026 ( Subtotal = $353,511 )
2026	2026	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/27/2026	NON-COMPETING CONTINUATION	$353,511
														Subtotal = $353,511

Issue Date FY: 2025 ( Subtotal = $406,597 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/6/2024	SUPPLEMENT FOR EXPANSION	$85,838
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/5/2024	NON-COMPETING CONTINUATION	$320,759
														Subtotal = $406,597

Issue Date FY: 2024 ( Subtotal = $434,139 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	5/2/2024	SUPPLEMENT FOR EXPANSION	$85,838
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/23/2024	NON-COMPETING CONTINUATION	$25,135
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/8/2023	NON-COMPETING CONTINUATION	$323,166
														Subtotal = $434,139

Issue Date FY: 2023 ( Subtotal = $391,193 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/28/2023	SUPPLEMENT FOR EXPANSION	$35,384
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/31/2023	NON-COMPETING CONTINUATION	$35,581
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/7/2022	NON-COMPETING CONTINUATION	$320,228
														Subtotal = $391,193

Issue Date FY: 2022 ( Subtotal = $358,526 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/18/2021	NEW	$358,526
														Subtotal = $358,526

Grand Total All Awards = $1,943,966

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Molecular and cellular mechanisms of HSV-1 assembly and egress

Award Number: R01NS117513

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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