Monday, June 30, 2025 6/30/2025

Immunogenetic determinants of HSV-2 infection and disease

Award Number: R21AI152559
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: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Immunogenetic determinants of HSV-2 infection and disease - PROJECT SUMMARY Infection with genital Herpes Simplex virus-2 (HSV-2) is life-long, and there is currently no cure or preventative vaccine despite substantial efforts. Furthermore, current anti-viral drugs such as acyclovir do not fully eliminate viral shedding or symptomatic genital ulcers for all patients, underscoring the need for new prevention and therapeutic strategies. There is considerable variation in rates of symptomatic and asymptomatic shedding as well as symptomatic disease between HSV-infected individuals, yet little understanding of the reasons underlying this variability. It is hypothesized that environmental and life-style factors such as stress, as well as genetic factors could play roles. Thus, we propose to use the Collaborative Cross in conjunction with a mouse model of vaginal HSV-2 infection to uncover novel genetic regions associated with HSV-2 shedding and disease, as well as with tissue-specific immune responses to infection. By defining host genetic regions that regulate these infection and disease-related phenotypes, we hope to pave the way for the identification and subsequent development of novel host-targeted and/or immune-based HSV therapies and prevention strategies that could lessen the burden of this global infectious disease as well as other infections transmitted via a mucosal surface. The Collaborative Cross (CC) is a population of recombinant inbred mouse strains with high levels of standing genetic variation, and was designed to allow for studies of the association between allelic variation in one or more genes and a phenotype of interest. We have successfully used the CC to screen for genetic loci involved in West Nile virus infection susceptibility and disease as well as immune phenotypes. We now propose to leverage our expertise with the CC as well as with the mouse model of HSV-2 to perform a screen of CC mouse strains for HSV-2 shedding, disease, and tissue inflammation phenotypes. Further, we will assess post-infection immune response phenotypes within both lymphoid tissues and tissue sites that are viral targets of disease, such as the genital tract and the central nervous system (CNS). We will use this data to perform quantitative trait loci (QTL) mapping to identify chromosomal regions associated with vaginal viral shedding rates and levels, virus- associated disease such as the formation of genital lesions and mortality, and immune cell responses at different times and in different tissues post-infection. Through this proposed work, we expect to identify novel HSV susceptibility alleles that could inform the rational design of host-targeted HSV treatments and prevention strategies. Additionally, it is increasingly recognized that immune cell phenotype and function can vary widely based on tissue location. This study will identify genetic regions associated with immune responses to infection in distinct tissue locations, including both lymphoid and mucosal tissues, to thus increase knowledge of the host genetic regulation of tissue-specific immune cell function following infection.


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: 2024 ( Subtotal = $0 )
2024	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	3/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/27/2022	NON-COMPETING CONTINUATION	-$208,907
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	3	5/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$208,907
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $220,578 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/13/2021	NON-COMPETING CONTINUATION	$220,578
														Subtotal = $220,578

Issue Date FY: 2020 ( Subtotal = $276,593 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	5/25/2020	NEW	$276,593
														Subtotal = $276,593

Grand Total All Awards = $497,171

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Immunogenetic determinants of HSV-2 infection and disease

Award Number: R21AI152559

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: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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