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Persistent HIV-1 expression and microglia dysfunction

Award Number: R01DA055488
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Persistent HIV-1 expression and microglia dysfunction - ABSTRACT/PROJECT SUMMARY Microglia are long-lived central nervous system (CNS)-resident innate immune cells that have critical immune surveillance functions and homeostatic functions in the brain including clearance of pathogens and maintaining integrity of neuronal synapses. Microglia are targeted by HIV, have been proposed to be a reservoir for HIV persistent infection and are mediators of HIV-associated inflammation and neuropathogenesis. Importantly, microglia dysfunction is proposed to contribute to HIV associated neurodegeneration and inflammation even when HIV replication is suppressed during antiretroviral treatments. The mechanisms, direct or indirect, that drive microglia to promote inflammation during HIV infection have not been elucidated. In this study, we will utilize a primary microglia-neuron coculture model derived from pluripotent stem cells to test the hypothesis that HIV in microglia establishes persistently infected microglia that express aberrant viral RNAs, including those that retain intronic sequences, which mediate inflammasome activation to drive microglia dysfunction, CNS inflammation and neuronal injury. Our preliminary data supporting our hypothesis includes results demonstrating that primary macrophages harbor defective HIV proviruses and, despite harboring deletions and mutations that attenuate virus production, generate HIV RNAs. Furthermore, our previous work established the potential role of HIV intron containing RNA in activating inflammatory activities in macrophages and microglia. Specific questions addressed in this proposal include: 1) what is the status of proviruses in HIV infected microglia; 2) what mechanisms drive persistent expression of HIV RNA in microglia; and 3) what are the mechanisms that trigger inflammasome activation in HIV-activated macrophages? Completion of this project will provide general insights into the impact of HIV-1 persistence and expression in the context of microglia. Importantly, these studies will provide insights into mechanisms that contribute to HIV-1 CNS comorbidities which persist even with ART and could lead to new targets and strategies for treatments that will improve the lives of people living with HIV.


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 = $729,537 )
2025	2025	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	5	5/7/2025	NON-COMPETING CONTINUATION	$729,537
														Subtotal = $729,537

Issue Date FY: 2024 ( Subtotal = $739,881 )
2024	2024	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	4	5/17/2024	NON-COMPETING CONTINUATION	$739,881
														Subtotal = $739,881

Issue Date FY: 2023 ( Subtotal = $739,881 )
2023	2023	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	5/31/2023	NON-COMPETING CONTINUATION	$739,881
														Subtotal = $739,881

Issue Date FY: 2022 ( Subtotal = $739,881 )
2022	2022	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	2	5/19/2022	NON-COMPETING CONTINUATION	$739,881
														Subtotal = $739,881

Issue Date FY: 2021 ( Subtotal = $759,381 )
2021	2021	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CENTER PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	7/9/2021	NEW	$759,381
														Subtotal = $759,381

Grand Total All Awards = $3,708,561

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Persistent HIV-1 expression and microglia dysfunction

Award Number: R01DA055488

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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