Tuesday, October 3, 2023 10/3/2023

Disabling the replication-competent HIV provirus in the reservoir by combined CRISPR-Cas action

Award Number: R01AI145045
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary. DNA can be targeted by the CRISPR- Cas (CC) genome editing tool, which was swiftly implemented in anti-HIV studies1-8. We confirmed potent HIV inhibition, but also demonstrated rapid virus escape from CC attack9. Inspection of the escape viruses indicated a role of the NHEJ enzyme, which repairs dsDNA breaks and introduces small insertions/deletions (indels) in the process. In other words, we described a novel viral escape route that is facilitated by a cellular DNA repair process. These results were confirmed by other labs10-21. A combinatorial CC attack against conserved sequences triggered HIV inactivation through hypermutation, quite different from the proposed excision route (Fig 1). Although provirus excision could be detected in our system, it occurred with a very low efficiency. Instead, CC attack generated hypermutated proviruses that apparently lost all replication potential. In other words, continuous CC action can functionally CURE HIV infected cells, leaving the cells with a graveyard of inactivated HIV proviruses. This surprise finding represents a major hallmark in HIV CURE studies. We now propose to first delineate the underlying mechanisms and variables that determine the outcome of CC attack (HIV excision versus hypermutation). This will allow us to formulate the best CURE strategy. At the same time we focus on the major obstacle towards a CURE: delivery of the gene therapeutics to cells that compose the HIV-reservoir. The CC and delivery tools will then be combined for in vivo CURE studies in the HIS mouse.


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: 2023 ( Subtotal = $506,574 )
2023	2023	ACADEMISCH MEDISCH CENTRUM	MEIBERGDREEF 9	AMSTERDAM				NLD	Allergy and Infectious Diseases Research	000	5	3/3/2023	NON-COMPETING CONTINUATION	$506,574


Issue Date FY: 2022 ( Subtotal = $536,971 )
2022	2022	ACADEMISCH MEDISCH CENTRUM	MEIBERGDREEF 9	AMSTERDAM ZUIDOOST	NOORD-HOLLAND			NLD	Allergy and Infectious Diseases Research	000	4	5/11/2022	NON-COMPETING CONTINUATION	$536,971


Issue Date FY: 2021 ( Subtotal = $521,590 )
2021	2021	ACADEMISCH MEDISCH CENTRUM	MEIBERGDREEF 9	AMSTERDAM ZUIDOOST	NOORD-HOLLAND			NLD	Allergy and Infectious Diseases Research	000	3	7/29/2021	NON-COMPETING CONTINUATION	$521,590


Issue Date FY: 2020 ( Subtotal = $524,697 )
2020	2020	ACADEMISCH MEDISCH CENTRUM	MEIBERGDREEF 9	AMSTERDAM ZUIDOOST	NOORD-HOLLAND	1105 AZ		NLD	Allergy and Infectious Diseases Research	000	2	3/12/2020	NON-COMPETING CONTINUATION	$524,697


Issue Date FY: 2019 ( Subtotal = $534,233 )
2019	2019	ACADEMISCH MEDISCH CENTRUM	MEIBERGDREEF 9	AMSTERDAM ZUIDOOST	NOORD-HOLLAND	1105 AZ		NLD	Allergy and Infectious Diseases Research	000	1	4/5/2019	NEW	$534,233


Grand Total All Awards = $2,624,065

Sum of Action Amount is $2,624,065;

Grand Total = $2,624,065

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Disabling the replication-competent HIV provirus in the reservoir by combined CRISPR-Cas action

Award Number: R01AI145045

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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