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Epigenetic Control of CD8 T-Cell Differentiation in Human Lymph Nodes

Award Number: R01AI145305
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: 02/07/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Epigenetic Control of CD8 T-Cell Differentiation in Human Lymph Nodes - PROJECT SUMMARY The development of potent antiretroviral therapies, now delivered as a single pill once a day, has transformed HIV infection into a chronic disease. Globally, over 19 million people are now on life-long treatment, and test- and-treat strategies as was well as oral PrEP have the ability to further reduce HIV transmissions. However, despite these remarkable advances, prolonged ART mediated suppression of plasma viral loads to undetectable levels does not eradicate the virus, which rapidly rebounds upon treatment interruption. The many logistical limitations and cost challenges that come with providing life-long care to those living with HIV highlights the need for novel strategies of controlling the virus in the absence of therapy. Emerging data indicate that lymph nodes are a major source of HIV persistence during ART mainly because infected T follicular helper cells are protected from immune elimination due to partial exclusion of cytotoxic CD8 T cells (CTL) from germinal centers (GC). The molecular mechanisms that regulate CXCR5 expression which allows CTL migration into GCs are not known, mainly due to the difficulty associated with obtaining lymph node samples for such studies. Through innovative recruitment strategies, we have now solved this problem. We propose to use stored lymph node samples obtained from persons identified and treated at the onset of plasma viremia, in many when plasma viral loads are less than 1,000 RNA copies/ml to investigate why CTLs are largely excluded from GCs. Our preliminary ATAC-Seq studies suggest that CXCR5 expression on lymph node CTLs is epigenetically regulated. To follow up on this observation we propose to conduct chromatin accessibility analysis and transcriptional profiling of sorted HIV-specific CD8 T cells to identify epigenetic mechanisms that regulate CXCR5 expression. Our experimental approach will involve pairwise chromatin accessibility and transcription analysis of sorted follicular and extrafollicular HIV-specific CD8 T cells. This strategy will help to identify novel epigenetic and transcription factors that are different between the two populations. Finally, we will manipulate some of the differentially expressed genes using exogenous agents namely cytokines and epigenetic modifying drugs to determine the optimal conditions to induce CXCR5 expression on CD8 T cells. Our results will lead to novel strategies for redirecting CTL to follicular areas where they are needed to kill HIV infected cells. If successful, our studies will lead to novel strategies for redirecting CTL to follicular areas to eradicate HIV infection as part of a cure strategy.


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 = -$1 )
2025	2023	AFRICA HEALTH RESEARCH INSTITUTE	719 UMBILO RD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	5	6/25/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2023 ( Subtotal = $141,744 )
2023	2023	KWAZULU NATAL RESEARCH INSTITUTE FOR TUBERCULOSIS AND HIV (K-RITH)	UKZN UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	5	1/31/2023	NON-COMPETING CONTINUATION	$141,744
														Subtotal = $141,744

Issue Date FY: 2022 ( Subtotal = $141,827 )
2022	2022	KWAZULU NATAL RESEARCH INSTITUTE FOR TUBERCULOSIS AND HIV (K-RITH)	UKZN UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	4	1/26/2022	NON-COMPETING CONTINUATION	$141,827
														Subtotal = $141,827

Issue Date FY: 2021 ( Subtotal = $143,738 )
2021	2021	KWAZULU NATAL RESEARCH INSTITUTE FOR TUBERCULOSIS AND HIV (K-RITH)	UKZN UMBILO ROAD	DURBAN				ZAF	Allergy and Infectious Diseases Research	000	3	2/8/2021	NON-COMPETING CONTINUATION	$143,738
														Subtotal = $143,738

Issue Date FY: 2020 ( Subtotal = $142,626 )
2020	2020	KWAZULU NATAL RESEARCH INSTITUTE FOR TUBERCULOSIS AND HIV (K-RITH)	UKZN UMBILO ROAD	DURBAN		4001		ZAF	Allergy and Infectious Diseases Research	001	2	7/31/2020	NON-COMPETING CONTINUATION	$0
2020	2020	KWAZULU NATAL RESEARCH INSTITUTE FOR TUBERCULOSIS AND HIV (K-RITH)	UKZN UMBILO ROAD	DURBAN		4001		ZAF	Allergy and Infectious Diseases Research	000	2	1/24/2020	NON-COMPETING CONTINUATION	$142,626
														Subtotal = $142,626

Issue Date FY: 2019 ( Subtotal = $144,652 )
2019	2019	KWAZULU NATAL RESEARCH INSTITUTE FOR TUBERCULOSIS AND HIV (K-RITH)	UKZN UMBILO ROAD	DURBAN		4001		ZAF	Allergy and Infectious Diseases Research	000	1	2/7/2019	NEW	$144,652
														Subtotal = $144,652

Grand Total All Awards = $714,586

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Epigenetic Control of CD8 T-Cell Differentiation in Human Lymph Nodes

Award Number: R01AI145305

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: 02/07/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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