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Determining the molecular mechanisms of HIV-1 maturation

Award Number: R01AI178846
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: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Determining the molecular mechanisms of HIV-1 maturation - Project Abstract Before a newly budded HIV-1 particle becomes fusogenic (and infective) it must undergo maturation. During maturation the contents of the virion transform from a spherical shell into a conical structure after a series of cleavages of the 55 kDa Gag polyprotein by the viral protease. Proteolytic processing starts at the site between the spacer peptide 1 (SP1) and the nucleocapsid (NC) and culminates in the separation of SP1 from the capsid protein (CA). The initial cleavage event effectively separates the NC-gRNA layer from the viral membrane inducing gRNA condensation. The last event activates a molecular switch that triggers a late maturation event, namely the assembly of the mature HIV-1 capsid around the ribonucleic protein. During maturation, the matrix protein (MA), that is embedded to the viral membrane via a myristoyl group, is cleaved from CA, resulting in reordering of the MA lattice and alteration of the composition of the lipid membrane. Although several structures of immature and mature CA and MA hexamers have been solved by sub tomogram averaging, the molecular mechanism connecting the multiple events that occur during HIV-1 maturation are still unclear. Here, we propose to utilize full-scale molecular dynamics simulations, integrating shaped-based coarse- grained and atomistic methods, to determine motion-structures that reveal the mechanistic details of HIV-1 virion maturation. Results from the simulations will inform the engineering of protein mutants for structural analysis and guide the experimental design of functional analyses and testing of hypotheses derived from the molecular simulations.


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 = $570,741 )
2025	2025	UNIVERSITY OF DELAWARE	550 S COLLEGE AVE	NEWARK	DE	19713	NEW CASTLE	USA	Allergy and Infectious Diseases Research	000	3	9/4/2025	NON-COMPETING CONTINUATION	$570,741
														Subtotal = $570,741

Issue Date FY: 2024 ( Subtotal = $577,308 )
2024	2024	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Allergy and Infectious Diseases Research	000	2	7/23/2024	NON-COMPETING CONTINUATION	$577,308
														Subtotal = $577,308

Issue Date FY: 2023 ( Subtotal = $613,684 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Allergy and Infectious Diseases Research	000	1	8/15/2023	NEW	$613,684
														Subtotal = $613,684

Grand Total All Awards = $1,761,733

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Determining the molecular mechanisms of HIV-1 maturation

Award Number: R01AI178846

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: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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