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Stress-Mediated Regulation of herpes simplex virus type 1 (HSV-1) Reactivation from Latency.

Award Number: R01NS111167
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Stress-Mediated Regulation of herpes simplex virus type 1 (HSV-1) Reactivation from Latency. - Project Summary Human alphaherpesvirus 1 (HSV-1), an important human pathogen, establishes life-long latency in neurons within trigeminal ganglia (TG) and central nervous system. Stress (acute or chronic) periodically triggers reactivation from latency in humans, culminating in virus shedding. Recurrent ocular disease or encephalitis occurs in certain people who undergo reactivation from latency. A synthetic corticosteroid dexamethasone, which mimics the effects of stress, triggers HSV-1 reactivation from latency in latently infected mice. Conversely, a glucocorticoid receptor (GR) antagonist significantly reduces reactivation from latency. GR and certain stress-induced transcription factors, including Krüppel like factor 4 (KLF4) and KLF15, synergistically transactivate key viral promoters. GR and KLF4 are “pioneer” transcription factors that bind silent heterochromatin, remodel chromatin, and activate transcription. A GRS229A mutant mouse expresses a GR mutant that has a serine to alanine mutation at position 229, which is crucial for activating transcription. Strikingly, female, but not male, GRS229A mice latently infected with HSV-1 shed significantly less infectious virus during reactivation from latency compared to aged matched wild-type parental C57BL/6 mice. Based on our ground-breaking studies, we hypothesize GR activation and pioneer transcription factors initiate early stages of reactivation from latency. For Specific Aim 1 (SA1), we will test whether HSV-1 reactivation from latency is impaired using a mouse strain (S134A-GR) that contains a serineàalanine mutation at amino acid 134, which must be phosphorylated for ligand-independent GR activation. SA1 will also test whether crosstalk between GR and additional NHRs mediate reactivation from latency in mice and human sensory neurons. Studies designed to identify sex-specific genes that regulate reactivation from latency in GRS229A, S134A-GR, or C57BL/6 mice will be examined in SA2. Studies in SA3 will test whether chromatin of key HSV-1 promoters is remodeled by pioneer factors (GR and KLF4) and other stress-induced transcription factors during early stages of reactivation from latency. These studies will provide new insight into the mechanism by which stress triggers reactivation from latency. Since acyclovir does not dramatically reduce reactivation and there are no HSV-1 vaccines, these studies will also provide new therapeutic strategies designed to reduce the incidence of HSV-1 reactivation from latency.


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 = $389,793 )
2026	2026	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/12/2026	COMPETING CONTINUATION	$389,793
														Subtotal = $389,793

Issue Date FY: 2024 ( Subtotal = $341,013 )
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/26/2024	NON-COMPETING CONTINUATION	$316,404
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$24,609
														Subtotal = $341,013

Issue Date FY: 2023 ( Subtotal = $351,560 )
2023	2023	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/8/2023	NON-COMPETING CONTINUATION	$351,560
														Subtotal = $351,560

Issue Date FY: 2022 ( Subtotal = $351,560 )
2022	2022	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/3/2022	NON-COMPETING CONTINUATION	$35,156
2022	2022	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/3/2022	NON-COMPETING CONTINUATION	$316,404
														Subtotal = $351,560

Issue Date FY: 2021 ( Subtotal = $351,560 )
2021	2021	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/22/2021	NON-COMPETING CONTINUATION	$351,560
														Subtotal = $351,560

Issue Date FY: 2020 ( Subtotal = $351,560 )
2020	2020	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/25/2020	NEW	$351,560
														Subtotal = $351,560

Grand Total All Awards = $2,137,046

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Stress-Mediated Regulation of herpes simplex virus type 1 (HSV-1) Reactivation from Latency.

Award Number: R01NS111167

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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