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HIV-1 Preintegration Trafficking and Nuclear Localization

Award Number: R01AI052014
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: 01/15/2003
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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HIV-1 Preintegration Trafficking and Nuclear Localization - PROJECT SUMMARY This longstanding NIH grant over its lifetime has made seminal discoveries on the mechanisms of intranuclear HIV-1 trafficking and nuclear localization. In prior funding cycles, we determined that the nuclear pore complex protein nucleoporin 153 interacted with the viral protein capsid to affect the translocation of incoming viral replication complexes into the cell nucleus and sites of viral DNA integration in the human genome. We also first identified the cellular alternate polyadenylation protein cleavage and polyadenylation specificity factor 6 (CPSF6) as a direct binding partner of the viral capsid and revealed an important role for this interaction in integration of the viral reverse transcript into active chromatin. Over the most recent funding cycle, our work has clarified that the capsid-CPSF6 interaction is critical for viral replication complexes to travel into the nuclear structure, where they colocalize with nuclear organelle structures that are known as nuclear speckles. Using novel bioinformatic tools, our work moreover revealed the significant preference for HIV-1 to integrate into regions of our genome that physically associate with nuclear speckles. In this way, our most recent research has clarified the granularity of nuclear architectural structure that most favors and most attracts HIV-1 to its chromosomal sites of integration. Moving forward, we will determine several unknown aspects of this fundamental virus-host interaction, including the mechanistic basis of CPSF6 action in HIV-1 intranuclear targeting as well as the functional consequences of mistargeting, wherein HIV-1 is known to uncharacteristically integrate into heterochromatic lamina-proximal sequences out towards the periphery of the nuclear structure. We furthermore will investigate the participations of other host factors that we have earmarked as behaving biochemically similar to CPSF6 for their roles in HIV-1 trafficking in the nucleus to preferred sites of integration. We will also investigate the functional consequences of these virus-host interactions in monocytic cell types, wherein HIV-1 replication complexes can be sensed by cellular innate machinery to counteract the infection process. The translational relevance of this basic scientific research is highlighted through the mechanism of action of capsid protein inhibitors such as lenacapavir, which are in late stage clinical trials and are known to inhibit the interaction of the HIV-1 capsid with Nup153 and CPSF6 proteins in vitro, and to induce HIV-1 integration retargeting in cells. Our proposed work in total will address fundamental aspects of virus-host interactions that occur during HIV-1 infection to shield the virus from sensing in innate immune cells, navigate integration to preferred genomic DNA sites, as well as the consequences of misguided integration on virus function and reactivation from latency.


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 = $0 )
2026	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	22	1/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,224,434 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	23	6/3/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,224,434
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	22	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,224,434

Issue Date FY: 2024 ( Subtotal = $612,217 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	22	5/20/2024	NON-COMPETING CONTINUATION	$612,217
2024	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	20	2/9/2024	COMPETING CONTINUATION	$91,111
2024	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	2/9/2024	NON-COMPETING CONTINUATION	-$91,111
														Subtotal = $612,217

Issue Date FY: 2023 ( Subtotal = $612,217 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	21	5/15/2023	NON-COMPETING CONTINUATION	$612,217
														Subtotal = $612,217

Issue Date FY: 2022 ( Subtotal = $638,417 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	20	5/31/2022	COMPETING CONTINUATION	$638,417
2022	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	5/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $638,417

Issue Date FY: 2021 ( Subtotal = $499,291 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	2/23/2021	NON-COMPETING CONTINUATION	$499,291
														Subtotal = $499,291

Issue Date FY: 2020 ( Subtotal = $499,291 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	18	2/6/2020	NON-COMPETING CONTINUATION	$499,291
														Subtotal = $499,291

Issue Date FY: 2019 ( Subtotal = $499,291 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	17	2/15/2019	NON-COMPETING CONTINUATION	$499,291
														Subtotal = $499,291

Issue Date FY: 2018 ( Subtotal = $522,706 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	16	1/26/2018	NON-COMPETING CONTINUATION	$522,706
														Subtotal = $522,706

Issue Date FY: 2017 ( Subtotal = $541,456 )
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	004	15	6/29/2017	COMPETING CONTINUATION	$172,125
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	15	3/9/2017	COMPETING CONTINUATION	$541,456
2017	2016	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	14	1/9/2017	EXTENSION WITH OR WITHOUT FUNDS	$60,295
2017	2016	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	14	6/29/2017	EXTENSION WITH OR WITHOUT FUNDS	-$172,125
2017	2015	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	13	1/9/2017	NON-COMPETING CONTINUATION	-$60,295
														Subtotal = $541,456

Issue Date FY: 2016 ( Subtotal = $437,500 )
2016	2016	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	14	2/5/2016	EXTENSION WITH OR WITHOUT FUNDS	$437,500
														Subtotal = $437,500

Issue Date FY: 2015 ( Subtotal = $437,500 )
2015	2015	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	13	2/10/2015	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2014 ( Subtotal = $437,500 )
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	12	6/4/2014	NON-COMPETING CONTINUATION	$43,750
2014	2014	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	12	2/4/2014	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $437,500

Issue Date FY: 2013 ( Subtotal = $411,250 )
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	11	2/11/2013	NON-COMPETING CONTINUATION	$393,750
2013	2013	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	11	6/1/2013	NON-COMPETING CONTINUATION	$17,500
														Subtotal = $411,250

Issue Date FY: 2012 ( Subtotal = $437,500 )
2012	2012	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	10	2/17/2012	COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2011 ( Subtotal = $411,033 )
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	9	2/15/2011	NON-COMPETING CONTINUATION	$373,666
2011	2011	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	9	6/7/2011	NON-COMPETING CONTINUATION	$37,367
														Subtotal = $411,033

Issue Date FY: 2010 ( Subtotal = $415,185 )
2010	2010	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	2/17/2010	NON-COMPETING CONTINUATION	$415,185
														Subtotal = $415,185

Issue Date FY: 2009 ( Subtotal = $419,378 )
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	7	6/23/2009	NON-COMPETING CONTINUATION	$41,938
2009	2009	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	2/6/2009	NON-COMPETING CONTINUATION	$377,440
														Subtotal = $419,378

Issue Date FY: 2008 ( Subtotal = $419,378 )
2008	2008	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	2/19/2008	NON-COMPETING CONTINUATION	$419,378
														Subtotal = $419,378

Grand Total All Awards = $11,449,696

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HIV-1 Preintegration Trafficking and Nuclear Localization

Award Number: R01AI052014

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: 01/15/2003

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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