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Probing real-time conformational dynamics and allosteric cooperativity of the HIV-1 envelope glycoprotein during virus entry

Award Number: R01AI181600
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: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Probing real-time conformational dynamics and allosteric cooperativity of the HIV-1 envelope glycoprotein during virus entry - Project Summary: The envelope (Env) glycoprotein exposed on the surface of HIV-1 virions is essential for virus entry into susceptible cells and is the primary target of neutralizing antibodies, small molecules, and fusion inhibitors. The structural dynamics of Env promote HIV-1 entering susceptible cells via membrane fusion and facilitate antibody evasion. However, a lack of knowledge about the time-resolved structural dynamics and allostery of Env impedes the attempts to comprehend the mechanisms by which Env enables virus entry and facilitates immune evasion. Env is trimeric, in which each protomer is composed of two subunits: exterior gp120 for binding to cellular receptors/coreceptors and membrane-anchored gp41 for driving fusion. Upon interacting with cellular receptors/coreceptors, gp120 undergoes large-scale conformational changes, further activating a series of fusion-promoting structural refolding in gp41. Refolding in gp41 progresses from a prefusion state through intermediates to the post-fusion that is generally believed to drive membrane fusion. Structures of Env have provided atomic details of Env conformations at fusion endpoints. However, substantial knowledge gaps in the Env-mediated fusion mechanism cannot be bridged by conventional structural tools. These gaps include time, sequence, reversibility, transitional paths, and transient intermediate steps of structural changes of Env. The proposed research is based on the hypothesis that Env is a highly cooperative dynamic machine in which conformational changes reflected in gp120 and gp41 during fusion occur in well-ordered spatial and temporal equilibrium. Single-Molecule Fluorescence Resonance Energy Transfer (smFRET) studies with fluorescent labels placed on gp120 demonstrated that native Env intrinsically interchanges between multiple conformations and has responsive conformational sampling to CD4 activation, neutralizing antibodies, and inhibitors. This project will elucidate spatiotemporal information of Env in its native state, with focused investigations on the less- studied gp41 and its association with gp120, and ultimately provide a time-resolved stepwise spatial framework of the fusion process. Multiple synergic methods, including smFRET in the context of intact virions, an integrated enhanced sampling molecular dynamics (MD)-smFRET, AI-guided multiscale simulations/modeling for mapping Env allostery, cell-based virological assays, and photophysical analysis will be used. The research is built upon recently established minimally invasive smFRET imaging of Env using genetic code expansion combined with click chemistry. It will be further extended to multi-perspective for monitoring gp120-gp41 associated cooperativity and capturing structural changes of gp41. The conformational dynamics of Env will be monitored from three different structural perspectives. Neutralizing antibodies and fusion inhibitors will be used to facilitate revealing conformational cooperativities of Env and spatiotemporally resolving individual fusion intermediates. The expected results will provide new insights about the time-resolved structural dynamics and allostery of Env that can inform the design of Env-centric interventions such as vaccines, antibody therapy, and anti-viral drugs.


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 = $434,727 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	000	3	1/6/2026	NON-COMPETING CONTINUATION	$434,727
														Subtotal = $434,727

Issue Date FY: 2025 ( Subtotal = $421,684 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	000	2	11/5/2024	NON-COMPETING CONTINUATION	$421,684
														Subtotal = $421,684

Issue Date FY: 2024 ( Subtotal = $459,227 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$43,473
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Allergy and Infectious Diseases Research	000	1	12/1/2023	NEW	$415,754
														Subtotal = $459,227

Grand Total All Awards = $1,315,638

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Probing real-time conformational dynamics and allosteric cooperativity of the HIV-1 envelope glycoprotein during virus entry

Award Number: R01AI181600

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: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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