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Modulation of retroviral uncoating by cellular factors

Award Number: R01AI087390
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: 02/15/2010
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Modulation of retroviral uncoating by cellular factors - Despite of a great deal of effort by public and private institutions, we don't have a prophylactic vaccine against HIV-1 or an eradication protocol to treat infected patients. Recently, laboratories all over the word have reported an increase in the transmission of HIV-1 strains that are resistant to one or more components of the antiretroviral (ART) cocktail. In order to find novel therapeutic targets, basic understanding of HIV-1 replication is urgently needed. Early steps in the replication of human immunodeficiency virus (HIV-1) involve delivery of the viral core into the cytoplasm of the host cell. The viral core is a conical structure composed of ~1500 monomers of the HIV-1 capsid protein, which houses the viral RNA genome. We studied HIV-1 uncoating, reverse transcription, and nuclear import by exploiting the ability of different cellular factors to affect early events of HIV-1 replication. “Uncoating” is the dissociation of monomeric capsids from the HIV-1 core. Proteins and drugs that destabilize the HIV-1 core and accelerate uncoating in the cytosol prevent reverse transcription. Consistent with the concept that reverse transcription is linked to uncoating, we have shown that genetic or pharmacologic inhibition of reverse transcription prevents uncoating. During the previous funding period, we found that cellular proteins that stabilize the HIV-1 core allow reverse transcription but not nuclear import. These results support a model in which the HIV-1 core is a “container” that holds the elements required for reverse transcription. Opening the “container” disrupts reverse transcription. Keeping the “container” closed allows completion of reverse transcription but prevents nuclear import. These results suggest that core stability is tightly modulated during infection. Cyclophilin A (CypA) accounts for up to 0.4% of cellular protein and interacts with the HIV-1 capsid and core. However, the role that CypA plays in HIV-1 infection is not known. Our preliminary data indicate that CypA depletion inhibits HIV-1 infection in primary CD4+ T cells by 100 fold, supporting the use of this model to understand the role of CypA in HIV-1 infection. We hypothesize that CypA functions as a central modulator of HIV-1 infection by controlling interactions between cellular factors and the HIV-1 core during the early steps of HIV-1 infection. With the expert support of Dr. Hultquist, Dr. Campbell, Dr. Luban and Dr. KewalRamani, the following specific aims will test this hypothesis. Aim 1 will determine the mechanisms through which CypA modulates HIV-1 infection in human primary CD4+ T cells. Aim 2 will determine the effects of CypA on the HIV-1 capsid in the nucleus. Aim 3 will examine the roles of other cyclophilins in HIV-1 replication. Aim 4 will determine the effects of the Nup358 cyclophilin domain (Cyp358) on HIV-1 nuclear import. This proposal will address two important questions on the HIV-1 field: 1) The role of CypA in HIV-1 replication, which has been elusive for 25 years, and 2) the role of nuclear capsid in HIV-1 productive infection.


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 = $528,657 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	17	3/7/2024	NON-COMPETING CONTINUATION	$475,791
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	17	5/23/2024	NON-COMPETING CONTINUATION	$52,866
														Subtotal = $528,657

Issue Date FY: 2023 ( Subtotal = $528,657 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	16	3/14/2023	NON-COMPETING CONTINUATION	$528,657
														Subtotal = $528,657

Issue Date FY: 2022 ( Subtotal = $528,657 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	15	3/22/2022	NON-COMPETING CONTINUATION	$528,657
														Subtotal = $528,657

Issue Date FY: 2021 ( Subtotal = $528,657 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	14	3/19/2021	NON-COMPETING CONTINUATION	$528,657
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	13	6/7/2021	COMPETING CONTINUATION	$124,638
2021	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	12	6/7/2021	NON-COMPETING CONTINUATION	-$124,638
														Subtotal = $528,657

Issue Date FY: 2020 ( Subtotal = $527,477 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	13	4/6/2020	COMPETING CONTINUATION	$527,477
2020	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	12	3/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $527,477

Issue Date FY: 2019 ( Subtotal = $417,500 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	12	3/1/2019	NON-COMPETING CONTINUATION	$417,500
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	11	2/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$60,311
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	004	11	5/2/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,305
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	10	5/2/2019	NON-COMPETING CONTINUATION	-$1,305
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	10	2/8/2019	NON-COMPETING CONTINUATION	-$60,311
														Subtotal = $417,500

Issue Date FY: 2018 ( Subtotal = $417,500 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	10	2/2/2018	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2017 ( Subtotal = $417,500 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	9	3/1/2017	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2016 ( Subtotal = $417,500 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Allergy and Infectious Diseases Research	000	8	2/26/2016	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2015 ( Subtotal = $417,500 )
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	002	6	9/10/2015	COMPETING CONTINUATION	-$201,925
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	000	6	2/19/2015	COMPETING CONTINUATION	$417,500
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Allergy and Infectious Diseases Research	003	7	9/10/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$201,925
2015	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	001	5	2/19/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $417,500

Issue Date FY: 2014 ( Subtotal = $410,850 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	001	5	6/6/2014	NON-COMPETING CONTINUATION	$41,085
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	000	5	1/24/2014	NON-COMPETING CONTINUATION	$369,765
														Subtotal = $410,850

Issue Date FY: 2013 ( Subtotal = $386,199 )
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	001	4	6/3/2013	NON-COMPETING CONTINUATION	$16,434
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	000	4	1/7/2013	NON-COMPETING CONTINUATION	$369,765
														Subtotal = $386,199

Issue Date FY: 2012 ( Subtotal = $410,850 )
2012	2012	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	000	3	1/27/2012	NON-COMPETING CONTINUATION	$410,850
														Subtotal = $410,850

Issue Date FY: 2011 ( Subtotal = $410,850 )
2011	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	000	2	1/19/2011	NON-COMPETING CONTINUATION	$373,500
2011	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	001	2	6/6/2011	NON-COMPETING CONTINUATION	$37,350
														Subtotal = $410,850

Issue Date FY: 2010 ( Subtotal = $415,000 )
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Allergy and Infectious Diseases Research	000	1	2/2/2010	NEW	$415,000
														Subtotal = $415,000

Grand Total All Awards = $6,763,354

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Modulation of retroviral uncoating by cellular factors

Award Number: R01AI087390

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: 02/15/2010

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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