Saturday, November 23, 2024 11/23/2024

Elucidating antiviral defenses against diverse immunodeficiency viruses using a novel, high-throughput CRISPR/Cas9 screening method.

Award Number: F30AI157898
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY The zoonotic transmission of viral pathogens from animals to humans contributes to the majority of emerging infectious diseases, which pose a substantial and increasing threat to human health. While host innate immunity—namely the production of Type I Interferon (IFN) and the subsequent production of Interferon Stimulated Genes (ISGS) with antiviral activities—plays an important role in determining viral tropism and limiting the cross-species transmission of viruses, much work remains on identifying and characterizing ISGs limiting viral tropism. Our lab has determined that while the human immunodeficiency virus (HIV-1) and non-human primate simian immunodeficiency viruses (SIV) are able to at least partly evade IFN-mediated defenses in cells from their cognate host, they remain exquisitely sensitive to such defenses in cells from unnatural hosts. Since HIV-1 and HIV-2 both arose from the cross-species transmission of diverse SIV species, the human and primate immunodeficiency viruses are a rich model system for studying the relationship between host innate immunity and viral adaptation. In order to identify human genes inhibiting SIV infection, we have modified a recently described high-throughput, CRISPR-based screening assay to identify human ISGs with activity against SIVmac239. Our preliminary data suggests that our model system is working as designed, as had identified a number of candidate genes that inhibit SIVmac infection in human cells. In Aim 1, we will determine the mechanism of action of novel ISGs with confirmed activity against SIVmac239. We will perform stepwise mechanistic studies to dissect the point of inhibition in the viral lifecycle. We will additionally perform co- immunoprecipitation and co-localization studies to identify viral components and cellular cofactors relevant to mechanism of inhibition. In Aim 2, we will use our established pipeline to screen for ISGs inhibiting diverse SIV strains. Preliminary data strongly suggests that we will be able to directly use the system we have developed to screen diverse strains of SIV. We will assess multiple SIV strains for sensitivity to IFN and screen those that are sensitive for inhibitory ISGs. We hypothesize that there will be both conserved and distinct inhibitory factors targeting the various SIV species. Combined, these approaches will reveal novel restriction factors that inhibit diverse SIVs in human cells, providing insight into the evolutionary adaptations that HIV-1 and HIV-2 made in order to successfully colonize humans.


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 = -$18,159 )
2025	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	10/21/2024	NON-COMPETING CONTINUATION	-$18,159
														Subtotal = -$18,159

Issue Date FY: 2024 ( Subtotal = $74,974 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	001	4	5/22/2024	NON-COMPETING CONTINUATION	$22,280
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	11/30/2023	NON-COMPETING CONTINUATION	$31,694
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	002	4	7/12/2024	SUPPLEMENT FOR EXPANSION	$21,000
														Subtotal = $74,974

Issue Date FY: 2023 ( Subtotal = $31,694 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	2/24/2023	NON-COMPETING CONTINUATION	$942
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	11/10/2022	NON-COMPETING CONTINUATION	$30,752
														Subtotal = $31,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	2	5/27/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	003	2	6/13/2022	NON-COMPETING CONTINUATION	$200
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	11/23/2021	NON-COMPETING CONTINUATION	$51,036
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	2	5/12/2022	NON-COMPETING CONTINUATION	$517
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	1	2/8/2021	NEW	$516
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	1	11/23/2020	NEW	$0
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	11/23/2020	NEW	$50,520
														Subtotal = $51,036

Grand Total All Awards = $191,297

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Elucidating antiviral defenses against diverse immunodeficiency viruses using a novel, high-throughput CRISPR/Cas9 screening method.

Award Number: F30AI157898

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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