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Roles of HIV-1 capsid-binding FG-motif containing cellular cofactors in infection

Award Number: R01AI162665
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: 02/08/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Roles of HIV-1 capsid-binding FG-motif containing cellular cofactors in infection - Abstract Early events in HIV-1 lifecycle, such as post-fusion trafficking of viral cores across the cytoplasm, through the nuclear pore complex (NPC) and into the nucleus, remain poorly understood due to limited information about virus-host interactions. Interactions of the core’s surface, which is composed of the capsid protein (CA) arranged into large hexameric lattices and exactly 12 pentamers, with a variety of host cell proteins that aid infection (dependency factors) are crucial for this journey. However, their full identity and molecular mechanisms of action remain largely unknown. Our preliminary studies resulted in the following two principal discoveries. 1) We have identified SEC24C as a new, crucial HIV-1 host dependency factor. SEC24C is a predominantly cytoplasmic protein that employs a phenylalanine-glycine (FG)-motif to specifically interact with the hexameric CA lattice at the hydrophobic pocket comprised of two adjoining subunits. These novel findings, coupled with the known roles of other CA-binding FG-motif containing cellular factors NUP153 and CPSF6 in nuclear import and integration site selection of HIV-1, suggest that these proteins collectively provide a dependable platform for continuous HIV-1 journey throughout different cellular compartments during the virus ingress to ensure productive infection. 2) We discovered a prion- like domain (PrLD)-mediated mechanism for avid binding of SEC24C, NUP153 and CPSF6 to hexameric CA lattices. Our preliminary cryo-EM and HDX-MS studies provide novel structural information indicating that, in addition to known CPSF6 FG peptide binding to the cognate CA hydrophobic pocket, PrLD-PrLD interactions enable polyvalent assembly of CPSF6 molecules along the extended lattices of adjoining CA hexamers. Our virology experiments further support an essential role of CPSF6 PrLD in functional virus- host interactions in infected cells. To extend these exciting, paradigm-shifting preliminary studies we propose the following three specific aims: Aim 1 will define a role of SEC24C in HIV-1 infection; Aim 2 will elucidate interplay between SEC24C and other CA-binding host factors; Aim 3 will determine the structural basis for avid recognition of hexameric HIV-1 CA lattices by FG-motif and PrLD containing cellular factors SEC24C, NUP153 and CPSF6. To accomplish these aims we have assembled a highly collaborative team with complementary expertise in virology, proteomics, biochemistry and X-ray crystallography (Kvaratskhelia), cryo-EM (Asturias), live cell microscopy (Melikian) and HDX-MS (Griffin). These studies are expected to uncover novel virus-host interaction mechanisms crucial for HIV-1 infection. Furthermore, elucidating structural determinants for functionally relevant interactions of SEC24C, NUP153 and CPSF6 to hexameric CA lattices will provide a new frontier in HIV-1 structural biology and improve our understanding of these virus-host interactions as an important therapeutic target.


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 = $774,370 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	5	12/29/2025	NON-COMPETING CONTINUATION	$774,370
														Subtotal = $774,370

Issue Date FY: 2025 ( Subtotal = $753,963 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	4	1/15/2025	NON-COMPETING CONTINUATION	$753,963
														Subtotal = $753,963

Issue Date FY: 2024 ( Subtotal = $780,112 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	3	1/8/2024	NON-COMPETING CONTINUATION	$702,100
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	002	3	8/21/2024	NON-COMPETING CONTINUATION	$0
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$78,012
														Subtotal = $780,112

Issue Date FY: 2023 ( Subtotal = $782,859 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	1/26/2023	NON-COMPETING CONTINUATION	$782,859
														Subtotal = $782,859

Issue Date FY: 2022 ( Subtotal = $813,266 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	2/8/2022	NEW	$813,266
														Subtotal = $813,266

Grand Total All Awards = $3,904,570

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Roles of HIV-1 capsid-binding FG-motif containing cellular cofactors in infection

Award Number: R01AI162665

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: 02/08/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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