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Mechanistic Study and Gene Targeting to Block HIV Assembly by IN-Binding Protein

Award Number: F31GM123537
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/16/2016
PERIOD OF PERFORMANCE END DATE: 03/15/2018

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Mechanistic Study and Gene Targeting to Block HIV Assembly by IN-Binding Protein - Despite major advances in treatment, Human Immunodeficiency Virus 1 (HIV-1) remains a significant public health issue that currently has no cure. Lifelong treatment is required due to the remaining latently infected cells. Unlike currently available drugs, a self-sustained therapeutic that targets events undergone by infected cells could potentially control the viral load in patients, leading to a functional cure. The HIV-1 life cycle consists of early events, the events from entry to proviral integration into the genome, and late events, which encompass transcription through budding and virion maturation. HIV-1 assembly, one of the late events, involves sequential assembly of Gag and Gag-Pol structural proteins along with HIV-1 genomic RNA to form assembly intermediate complexes, that eventually reach the plasma membrane to bud out as infectious virions. While much has been studied about assembly and viral determinants required for these events, the nature of assembly intermediates and the association of viral and cellular protein in these complexes is not well understood. Furthermore, while Gag is the major viral structural protein that is involved in assembly, Gag-Pol, which is incorporated at 1:20 ratio to that of Gag, also plays a role in these events. Mutations in Pol portion of Gag-Pol such as integrase (IN) and reverse transcriptase (RT) have been shown to interfere with the assembly events. The role of Gag-Pol or the host factors associated with Pol is largely unknown at this point. My project is focused on understanding of the role of a Pol-binding host factor in assembly and use this knowledge to develop therapeutics to inhibit assembly. . A fragment of the HIV-1 IN-binding host protein, INI1/hSNF5, has been previously shown to inhibit HIV- 1 late events prior to budding. While it is known that the minimal IN-binding fragment of INI1/hSNF5 (termed S6) inhibits late events prior to budding, the exact stage or the mechanism is unknown. In this proposal, I propose (1) examining assembly intermediate complexes to determine if this inhibitory fragment affects assembly complex formation and (2) site-specifically inserting DNA coding for this fragment into the genome of T-cells and assessing off-target effects and ability to inhibit HIV-1 particle production. Determining the effects of S6 on assembly intermediates will shed light on mechanisms of early assembly and improve our knowledge of the role of IN-binding proteins in HIV-1 assembly. Gene therapy approaches to express S6 in T cells hold promising therapeutic potential for HIV-1. Inserting S6 site-specifically, using CRISPR/Cas9, a targeted nuclease that precisely modifies genomes, to inhibit assembly not only provides a novel approach to inhibit assembly, but also helps improve our knowledge of genome engineering to inhibit HIV-1 replication.


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: 2021 ( Subtotal = -$1,055 )
2021	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	2	12/28/2020	NON-COMPETING CONTINUATION	-$1,055
														Subtotal = -$1,055

Issue Date FY: 2019 ( Subtotal = -$22,294 )
2019	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	2	4/8/2019	NON-COMPETING CONTINUATION	-$22,294
														Subtotal = -$22,294

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	2	3/28/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $44,044 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Biomedical Research and Research Training	000	2	8/30/2017	NON-COMPETING CONTINUATION	$44,044
														Subtotal = $44,044

Issue Date FY: 2016 ( Subtotal = $43,576 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Biomedical Research and Research Training	000	1	9/15/2016	NEW	$43,576
														Subtotal = $43,576

Grand Total All Awards = $64,271

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Mechanistic Study and Gene Targeting to Block HIV Assembly by IN-Binding Protein

Award Number: F31GM123537

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/16/2016

PERIOD OF PERFORMANCE END DATE: 03/15/2018

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