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Coupling Epitranscriptomics to Molecular Disease Mechanisms and Nucleic Acid Therapeutics in Persistent Residual HIV Infection

Award Number: R61AI169661
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Human immunodeficiency virus (HIV) is a highly manageable infection when treated with combination anti-retroviral therapy (cART). However, it is not yet curable and people living with HIV (PLWH) taking cART suffer from suboptimal immune health and reduced quality of life long-term. A leading cause of ongoing health concerns is persistent, residual infection. Persistently infected T-cells of PLWH that take cART still produce viral RNA and proteins, as well as defective proviruses, that can chronically activate the immune system despite undetectable viral loads. A better understanding of the biology and metabolism of HIV RNA and gene expression in PLWH taking cART could unlock additional therapeutic strategies to reduce viral gene products and improve quality of life. Cellular RNA and viral RNA can be subjected to a variety of post-transcriptional chemical modifications. These modifications modulate or fine-tune molecular interactions and thereby control gene expression and function through RNA processing, turnover, localization, or translation. Covalent base modification and its effects on RNA regulation at a broad level beyond the four canonical bases is often termed epitranscriptomics. The intimate relationship between RNA modification and RNA metabolism is becoming better appreciated. However, manipulating this process for therapeutic treatment of HIV and persistent infection in PLWH taking cART requires a deeper understanding of HIV epitranscriptomics. Here we propose systematic characterization and manipulation of HIV-1 RNA transcripts in model and patient T-cells. In the R61 phase, we will utilize three powerful sequencing methodologies (total RNA-seq, ribosome profiling, and nanopore direct RNA sequencing) to globally characterize the abundance, processing, translation, and modification status of both viral and host RNA in T-cells during cART. These experiments will include selection of persistently infected T-cells from PLWH taking cART. We will target several known modifications via enzyme knockouts and nanopore sequencing. These experiments will characterize HIV-1 RNA chemical modifications of potential significance and identify those with high a likelihood of impacting HIV RNA and protein loads in T-cells. In the R33 phase, we will use chemically modified oligonucleotides to alter modifications of high interest by blocking or directing site-specific modification. This will include oligonucleotides that sterically block modification or guide new modification, both therapeutic modalities that are maturing rapidly. Chemically modified oligonucleotides will provide a proof-of-concept for epiptranscriptome manipulation as a potential therapeutic approach while offering nucleic acid therapeutic candidates.


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 = $543,629 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	002	4	3/12/2024	NON-COMPETING CONTINUATION	$480,887
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	003	4	5/23/2024	NON-COMPETING CONTINUATION	$53,432
2024	2023	BOARD OF TRUSTEES OF SOUTHERN ILLINOIS UNIVERSITY	900 S NORMAL AVE	CARBONDALE	IL	62901	JACKSON	USA	Allergy and Infectious Diseases Research	001	2	11/3/2023	NON-COMPETING CONTINUATION	-$239,498
2024	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	3	11/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$248,808
														Subtotal = $543,629

Issue Date FY: 2023 ( Subtotal = $587,812 )
2023	2023	SOUTHERN ILLINOIS UNIVERSITY	900 SOUTH NORMAL AVE	CARBONDALE	IL	62901	JACKSON	USA	Allergy and Infectious Diseases Research	000	2	3/16/2023	NON-COMPETING CONTINUATION	$587,812
														Subtotal = $587,812

Issue Date FY: 2022 ( Subtotal = $654,356 )
2022	2022	SOUTHERN ILLINOIS UNIVERSITY	900 SOUTH NORMAL AVE	CARBONDALE	IL	62901	JACKSON	USA	Allergy and Infectious Diseases Research	000	1	4/28/2022	NEW	$654,356
														Subtotal = $654,356

Grand Total All Awards = $1,785,797

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Coupling Epitranscriptomics to Molecular Disease Mechanisms and Nucleic Acid Therapeutics in Persistent Residual HIV Infection

Award Number: R61AI169661

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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