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The Guts of HIV: Innate Immune Dysregulation as a Central Mechanism of Gastrointestinal and Liver Disease in HIV-1-infected Individuals

Award Number: R01DK108353
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): Liver disease (LD) has risen as a major cause of morbidity and mortality in antiretroviral therapy (ART)-treated HIV-1-infected individuals. A growing body of evidence suggests that HIV-1 alters and accelerates the pathologic processes driving LD via systemic inflammation; however, the role of neutrophils and innate immune dysregulation in these processes has not been evaluated. This application proposes that innate immune dysregulation mediated by changes in macrophage and neutrophil populations in gut- associated lymphoid tissue (GALT) and liver plays a fundamental role in HIV-1 disease progression. Neutrophils, the most abundant immune cell population in the body, are specifically geared for a sensitive detection of invading microbial and viral pathogens. GALT epithelial damage in both HIV-1 and SIV infections is temporally and spatially associated with a significant accumulation of neutrophils that directly contribute to mucosal damage. IL-17 serves as a master regulator of neutrophil function and, in conjunction with IL-10, it is required for an induction of anti-inflammatory macrophages that clear apoptotic neutrophilic infiltrates via efferocytosis and promote healing and resolution of local and systemic inflammation. The first underlying hypothesis of this proposal is that the depletion of IL-17-producing cells in the GALT of HIV-1-infected individuals blocks the induction of anti-inflammatory efferocytic tissue macrophages and causes polarization towards pro-inflammatory phenotype. This results in an accumulation of activated neutrophils that undergo NETosis and drive tissue damage in intestinal mucosa. Factors released as a result of ongoing GALT inflammation induce systemic recruitment of a population of activated neutrophils with specific phenotype, expression profile, and high capacity for NETosis. The second principal hypothesis is that HIV-1 infection is associated with a significantly decreased frequency of Kupffer cells (KCs) exhibiting anti-inflammatory phenotype and a significant shift towards blood monocyte-derived proinflammatory KCs. This state is not reversed following ART, possibly due to the depletion of self-renewing tissue-resident KC progenitors. Activated neutrophils interact with Kupffer cells and platelet and undergo NETosis in liver microvasculature. In the course of HIV-1 infection, this mechanism causes chronic liver inflammation, portal hypertension, activation of hepatic stellate cells, and results in a progression to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Thus, we propose that two simultaneous hits to innate immune populations in primary and secondary mucosal firewalls, the GALT and the liver, drive disease progression in HIV-1/AIDS. We propose to determine the effect of neutrophil activation and innate immune dysregulation in GALT and liver on the progression of LD in ART- treated HIV-1-infected individuals. Importantly, since functional dysregulation of neutrophil population and neutrophil-macrophage interaction can be pharmacologically targeted, understanding of the underlying pathogenic mechanisms will lead to novel treatment approaches in HIV-1 infection and other chronic inflammatory conditions.


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: 2023 ( Subtotal = $0 )
2023	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $324,999 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/15/2019	NON-COMPETING CONTINUATION	$324,999
														Subtotal = $324,999

Issue Date FY: 2018 ( Subtotal = $324,999 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/2/2018	NON-COMPETING CONTINUATION	$324,999
														Subtotal = $324,999

Issue Date FY: 2017 ( Subtotal = $324,999 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/16/2017	NON-COMPETING CONTINUATION	$324,999
														Subtotal = $324,999

Issue Date FY: 2016 ( Subtotal = $324,999 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/22/2016	NON-COMPETING CONTINUATION	$324,999
														Subtotal = $324,999

Issue Date FY: 2015 ( Subtotal = $324,999 )
2015	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/23/2015	NEW	$324,999
														Subtotal = $324,999

Grand Total All Awards = $1,624,995

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The Guts of HIV: Innate Immune Dysregulation as a Central Mechanism of Gastrointestinal and Liver Disease in HIV-1-infected Individuals

Award Number: R01DK108353

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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