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Sex difference in intestinal immune dysfunction, SHIV infection and reservoir

Award Number: R01DK130769
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Sex difference in intestinal immune dysfunction, SHIV infection and reservoir - PROJECT SUMMARY Gastrointestinal malfunctions and immune activation remain significant health issues for people living with HIV/AIDS in the era of anti-retroviral therapy (ART). Immune activation fuels HIV reservoirs that are established early during infection and support virus rebound after ART interruption (ATI). Increasing evidence points toward sex differences in HIV pathogenesis, disease progression, and persistence. Identifying sex-specific immune parameters associated with viral persistence and rebound will be critical to our long term goal of developing personalized therapeutic strategies to reliably halt HIV-associated chronic diseases, and to target HIV reservoirs. In subjects without ART, women have higher levels of immune activation than men and have a higher risk of developing AIDS. Sex differences in immune activation in HIV-infected subjects on ART are less definitive, possibly due to confounding factors, including gender (involving social/behavior factors) differences in seeking treatment. Recent evidence identifying estrogen receptor 1 as a key regulator of HIV latency in CD4+ T cells suggests the involvement of estrogen signaling in sex-based differences in HIV persistence. However, the role of estrogen in HIV persistence in vivo remains unknown, as estrogen induces type I IFNs and other pro- inflammatory cytokines, resulting in immune activation. Research in this area has been lacking a reliable animal model. In that regard, we have developed a rhesus macaque (RM) model that mimics key features of human HIV infection providing promising avenues for pursuing sex-based difference studies. The model, which employs R5 SHIV C109 intrarectal challenge, displays a spectrum of disease outcomes similar to human AIDS. In this model, fast disease progression occurs in females only, and is accompanied by an uncontrolled robust mucosal immune response. All male RMs tested to date exhibit normal (slow/chronic) progression. We hypothesize that kinetics and magnitude of immune dysregulation that drive viral replication, persistence, and rebound exhibit sex-based differences and that estrogen may partially contribute to sex difference in immune responses and viral persistence. We will determine sex-specific immune cellular and molecular determinants relevant to HIV reservoirs and rebound longitudinally. The contribution of estrogen to sex differences in immune regulation and viral persistence will also be examined. The proposed work is significant because it promises to provide new insights into the cross-talk between intestinal immune activation and viral persistence that are differentially regulated in male and female RMs, which will be critical for developing personalized therapeutic strategies to reliably halt HIV-associated chronic disease, and to target HIV reservoirs.


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 = $732,404 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/2/2024	NON-COMPETING CONTINUATION	$732,404
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	7/18/2024	NON-COMPETING CONTINUATION	$0
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$531,277
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/16/2024	NON-COMPETING CONTINUATION	-$531,277
														Subtotal = $732,404

Issue Date FY: 2023 ( Subtotal = $762,285 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$762,285
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $762,285

Issue Date FY: 2022 ( Subtotal = $761,967 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/28/2022	NON-COMPETING CONTINUATION	$761,967
														Subtotal = $761,967

Issue Date FY: 2021 ( Subtotal = $777,641 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/5/2021	NEW	$777,641
														Subtotal = $777,641

Grand Total All Awards = $3,034,297

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Sex difference in intestinal immune dysfunction, SHIV infection and reservoir

Award Number: R01DK130769

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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