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Long-term Effects of IDU, HIV, HCV and the Impact of HCV Cure on Immune Activation and Liver Fibrosis in Aging Women

Award Number: R01DA044111
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Our overall goal is to determine the long-term consequences of chronic HIV/HCV coinfection as a result of injection drug use (IDU) and the impact of HCV cure on the relationship of liver fibrosis and immune activation/ dysregulation in reproductively aging HIV-infected women. Liver disease with accelerated liver fibrosis is a major cause of death in HIV/HCV coinfected adults. Global immune activation may partly explain this accelerated liver fibrosis. With the advent of interferon-free direct-acting antiviral agents (DAA), a decrease in the burden of liver disease is expected. It is unknown if, after HCV cure, HIV-associated immune dysfunction impacts liver fibrosis or if residual liver injury affects immune recovery in reproductively aging HIV/HCV-coinfected women. Estrogen depletion is associated with increased immune dysfunction and metabolic disruptions, including visceral obesity, which could impact liver fibrosis. HCV infection has a major impact on immunopathogenesis of HIV and HCV disease. Our studies show that coinfected women with liver disease as compared to coinfected women without liver disease, have increased activated CD4+ T cells, and changes in immune regulatory and maturational pathways critical for immune homeostasis, including regulatory (Treg), senescent, effector memory and effector T cells. Coinfected women also have higher levels of transforming growth factor-ß (TGF-ß), an immunosuppressive cytokine critical for Treg differentiation and an important regulator of liver inflammation and fibrosis, as well as IL- 7, which promotes HIV persistence, stimulates HIV replication and HIV reservoirs, and promotes fibrogenesis, compared to HIV-monoinfected women. Our central hypotheses are that after HCV cure, HIV/HCV- coinfected women, who are aging, will have impaired liver fibrosis regression, because of HIV- associated immune dysregulation and increased risk of metabolic perturbations including hepatic steatosis (or fatty liver). The specific aims are to: (1) Longitudinally examine the short and long-term effects of HIV and menopause on liver fibrosis after HCV cure in aging HIV/HCV-coinfected women and (2) Determine if liver fibrosis impacts immune activation and dysregulation after HCV cure in HIV/HCV-coinfected women. HCV- monoinfected, HIV-monoinfected and uninfected women will serve as controls. We plan to use medication, menopause, metabolic, and liver fibrosis data, and biorepository samples from the Women's Interagency HIV Study (WIHS), to accomplish our aims. State- of- the- art clinical and laboratory technologies will evaluate liver fibrosis and steatosis severity and gene-signature expression to elucidate pathways of immune activation and dysregulation assessed simultaneously with cellular phenotypic and soluble biomarkers. The WIHS provides a unique opportunity to tease out the complex contributions of HIV, HCV, liver injury and estrogen depletion on immunologic markers in women. The proposed studies will help us understand if estrogen depletion blunts recovery of liver injury after HCV cure and if residual liver injury affects HIV-associated immune activation/dysregulation. This will help inform strategies for prevention and treatment of liver fibrosis.


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	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	5	12/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	5	2/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $672,140 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	5	2/23/2021	NON-COMPETING CONTINUATION	$672,140
														Subtotal = $672,140

Issue Date FY: 2020 ( Subtotal = $684,441 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	4	2/4/2020	NON-COMPETING CONTINUATION	$684,441
														Subtotal = $684,441

Issue Date FY: 2019 ( Subtotal = $694,955 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	3	2/21/2019	NON-COMPETING CONTINUATION	$694,955
														Subtotal = $694,955

Issue Date FY: 2018 ( Subtotal = $705,013 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	001	2	4/26/2018	NON-COMPETING CONTINUATION	$70,502
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	2	2/14/2018	NON-COMPETING CONTINUATION	$634,511
														Subtotal = $705,013

Issue Date FY: 2017 ( Subtotal = $731,445 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Drug Abuse and Addiction Research Programs	000	1	3/28/2017	NEW	$731,445
														Subtotal = $731,445

Grand Total All Awards = $3,487,994

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Long-term Effects of IDU, HIV, HCV and the Impact of HCV Cure on Immune Activation and Liver Fibrosis in Aging Women

Award Number: R01DA044111

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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