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Extracellular vesicles as the vehicles for promoting liver injury induced by HIV and alcohol

Award Number: R01AA027189
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Extracellular vesicles as the vehicles for promoting liver injury induced by HIV and alcohol - PROJECT SUMMARY/ABSTRACT Liver disease is the second-leading cause of mortality in HIV-infected patients, but its significance as a component of this infection requires further study. HIV infection damages liver cells, including resident macrophages (i.e., Kupffer cells) and hepatocytes. HIV-induced hepatotoxicity is potentiated by second hits, including alcohol. Alcohol consumption enhances the pathological features of HIV infection by increasing viremia, suppressing immune responses, promoting non-adherence to treatment, and causing poor HIV treatment outcomes. In addition, antiretroviral therapy (ART) is less effective in individuals who consume large quantities of alcohol, and certain drugs also provide hepatotoxic effects, leading to treatment cessation. Meanwhile, it is now clear that the liver plays an important role in the pathogenesis of HIV infection. It is possible that in HIV- infected alcohol abusers, the dissemination of infection and liver pathology results from cell-to-cell communication via extracellular vesicles (EVs), including apoptotic bodies (ABs) and exosomes containing viral nucleic acids, miRNAs as well as HIV- and alcohol-modified host cell cargos, which promote liver injury. Moreover, EVs from liver cells can spread inflammation to other organs. In this study, we hypothesize that ethanol metabolism amplifies HIV-triggered communication between hepatocytes and macrophages via EVs, thereby promoting liver inflammation and fibrosis. Furthermore, extrahepatic systemic distribution of these EVs may contribute to the systemic spread of HIV and dissemination of inflammation to other organs. This hypothesis will be tested in the following three Specific Aims: 1. Examine potentiating effects of alcohol on HIV-induced hepatocyte death and the role of large extracellular vesicles (i.e., apoptotic bodies) in promoting liver inflammation by macrophages. 2. Define how alcohol accelerates HIV-induced exosome release from hepatocytes and the role of exosomes in cross-talk between hepatocytes and macrophages in the development of liver inflammation 3. Elucidate the contribution of EVs to liver injury caused by both HIV-infection and ethanol consumption in vivo This pre-clinical investigation will provide the foundation for future clinical trials and translation. Furthermore, these findings could be readily translated to clinical practice by discovering potential biomarkers of liver injury progression, which accompany HIV-infection in those who abuse alcohol. By blocking EV release, we will seek additional treatment modalities that prevent the development of liver disease and systemic inflammation.


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: 2025 ( Subtotal = -$7,947 )
2025	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Alcohol Research Programs	000	5	6/9/2025	NON-COMPETING CONTINUATION	-$7,947
														Subtotal = -$7,947

Issue Date FY: 2023 ( Subtotal = $516,042 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	5	1/25/2023	NON-COMPETING CONTINUATION	$516,042
														Subtotal = $516,042

Issue Date FY: 2022 ( Subtotal = $513,541 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	001	4	2/1/2022	NON-COMPETING CONTINUATION	$462,185
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	002	4	6/22/2022	NON-COMPETING CONTINUATION	$51,356
2022	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	3	2/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $513,541

Issue Date FY: 2021 ( Subtotal = $525,723 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	3	2/17/2021	NON-COMPETING CONTINUATION	$525,723
														Subtotal = $525,723

Issue Date FY: 2020 ( Subtotal = $515,878 )
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	2	1/29/2020	NON-COMPETING CONTINUATION	$515,878
														Subtotal = $515,878

Issue Date FY: 2019 ( Subtotal = $529,043 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	1	2/8/2019	NEW	$529,043
														Subtotal = $529,043

Grand Total All Awards = $2,592,280

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Extracellular vesicles as the vehicles for promoting liver injury induced by HIV and alcohol

Award Number: R01AA027189

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/10/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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