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Modulation of epigenetic programming of tissue resident macrophage lineages to impact HIV-1 infection, maintenance, and persistence.

Award Number: R01AI176575
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Modulation of epigenetic programming of tissue resident macrophage lineages to impact HIV-1 infection, maintenance, and persistence. - Project Summary / Abstract It is only recently that the field became aware that certain tissue resident macrophages, including alveolar macrophages and microglial cells, are fetal stem cell derived lineages that behave markedly differently from blood monocyte derived macrophages. With such knowledge we need revisit the role of tissue resident macrophages as HIV-1 reservoirs and their contribution to viral persistence. We have shown that regulatory pathways in infected macrophages, such as pro-survival pathways, can be inhibited by targeting specific lncRNAs, thus driving selective cell death in infected but not uninfected macrophages. Such observations lay the groundwork for eradication of HIV-1 reservoirs, however, biologics, such as lncRNAs, are not as tractable as small molecule inhibitors to progress into therapeutics. We have extensive, documented expertise in macrophage biology in both mouse and human lung, and we have maintained a productive anti-TB drug discovery program based on phenotypic screening for compounds active in infected macrophages. With this expertise we propose the identification and functional characterization of small molecule epigenetic inhibitors capable of modifying host macrophage programming to drive selective induction of cell death in specific myeloid cell lineages, and probing the underlying mechanism(s). Our Specific Aims are: 1. Phenotypic Profiling HIV-1 infected HMDMs and AMs by transcriptional analysis. We will conduct transcriptional profiling on HIV-1 infected HMDMs and AMs to assess the diversity of the cellular responses to infection in both active and latent infection states in the two lineages. 2. Screening small molecule inhibitors of epigenetic programming in experimental infection in HMDMs and AMs, and in HC69.5 microglial cells. We have a library of 735 small molecule epigenetic inhibitors and will screen this compound collection against HIV-1 infected HMDMs, AMs, and against the immortalized human microglial cell line HC69.5, with the emphasis on identifying compounds that drive cell death across the different macrophage lineages and infection models. 3. Progressing hits through mode-of-action studies to identify actionable compounds. We propose analysis of HIV-1/macrophage biology prioritizing compounds that induce cell death in HIV-1 infected macrophages. Finally, to evaluate candidate compounds for their ability to drive cell death and suppress viral persistence we will assess activity through ex vivo drug treatment and cell survival and viral outgrowth from AMs from viremic HIV-1 positive human donors in Malawi.


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: 2026 ( Subtotal = $482,843 )
2026	2026	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	4	4/7/2026	NON-COMPETING CONTINUATION	$482,843
														Subtotal = $482,843

Issue Date FY: 2025 ( Subtotal = $482,843 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	3	8/15/2025	NON-COMPETING CONTINUATION	$482,843
														Subtotal = $482,843

Issue Date FY: 2024 ( Subtotal = $676,923 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	2	3/15/2024	NON-COMPETING CONTINUATION	$676,923
														Subtotal = $676,923

Issue Date FY: 2023 ( Subtotal = $695,223 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	4/6/2023	NEW	$695,223
														Subtotal = $695,223

Grand Total All Awards = $2,337,832

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Modulation of epigenetic programming of tissue resident macrophage lineages to impact HIV-1 infection, maintenance, and persistence.

Award Number: R01AI176575

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/06/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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