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Structural definition of CD4-induced HIV-1 Env conformational changes required for infection

Award Number: R01AI145687
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: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Structural definition of CD4-induced HIV-1 Env conformational changes required for infection - The HIV-1 envelope glycoprotein (Env), a homotrimer of gp120-gp41 heterodimers, mediates viral entry into host cells. The gp120 subunit engages host receptors, while the gp41 subunit contains a fusion peptide (FP) that is inserted into the host membrane to induce host and virus membrane fusion. Prior to its binding to host receptors, the HIV-1 Env is characterized by a closed configuration with gp120 protomers packed against each other and the gp41 subunit, while the highly conserved and immunodominant coreceptor-binding region at the Env trimer apex remains occluded by packing of the first and second (V1V2) as well as the third (V3) variable loops. At the trimer base, FP comprises a hydrophobic stretch of about 20 amino acids at the gp41 N terminus that is accessible for antibody binding in the closed configuration of Env. FP is a site of vulnerability to broadly neutralizing antibodies (bnAbs) and thus of vaccine focus. Until recently, two distinct structural configurations of the FP were defined in the literature, one that is antibody accessible in the pre- fusion closed Env and a second that is sequestered within a gp41-gp120 pocket in a partially or fully open CD4-induced Env. We recently described a functional intermediate state in atomic level details where the FP remains accessible to antibody binding despite substantial receptor binding mediated Env opening. In the study, Aim 1 will focus on the early stages of Env opening, including the role that the unique FP configuration in HIV-1 plays in the metastability of the pre-fusion, pre-receptor, closed Env and how this impacts the Env conformational landscape. Aim 2 will focus on detailed characterization of a newly defined functional intermediate state. Aim 3 will focus on later stages of Env opening where the FP gets buried within a hydrophobic core and is no longer available for antibody binding. These studies will advance our understanding of the HIV-1 entry mechanism and inform structure-based immunogen and drug design. The scientific premise of this grant is that the FP is a critical component of the HIV-1 entry machinery that determines virus attachment. Understanding the mechanistic basis of the movement of the FP during the entry process is thus critical to our understanding of HIV-1 biology. A mechanistic understanding of subsequent conformational changes and the intermediate states uncovered in the process will facilitate the development of intervention strategies that include immunogen design for HIV-1 vaccine efforts and drug design for novel cure AIDS strategies to eliminate the latent pool of HIV-1-infected CD4 T cells. The innovation in this grant derives from our discovery of a novel receptor-bound Env intermediate that shows substantial opening yet can bind a FP-directed antibody. The proposed studies will improve our understanding of HIV-1 entry and will inform vaccine and therapeutics development.


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 = $807,065 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	6	7/25/2025	COMPETING CONTINUATION	$807,497
2025	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	5/22/2025	NON-COMPETING CONTINUATION	-$432
														Subtotal = $807,065

Issue Date FY: 2023 ( Subtotal = $761,299 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	5	1/12/2023	NON-COMPETING CONTINUATION	$770,818
2023	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	3	6/23/2023	SUPPLEMENT FOR EXPANSION	-$9,519
														Subtotal = $761,299

Issue Date FY: 2022 ( Subtotal = $779,673 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	4	1/19/2022	NON-COMPETING CONTINUATION	$779,673
														Subtotal = $779,673

Issue Date FY: 2021 ( Subtotal = $1,510,467 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	1/22/2021	NON-COMPETING CONTINUATION	$739,174
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	3	1/26/2021	SUPPLEMENT FOR EXPANSION	$771,293
														Subtotal = $1,510,467

Issue Date FY: 2020 ( Subtotal = $1,466,173 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	1/28/2020	NON-COMPETING CONTINUATION	$733,183
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	001	2	5/21/2020	SUPPLEMENT FOR EXPANSION	$732,990
														Subtotal = $1,466,173

Issue Date FY: 2019 ( Subtotal = $758,709 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	1/25/2019	NEW	$758,709
														Subtotal = $758,709

Grand Total All Awards = $6,083,386

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Structural definition of CD4-induced HIV-1 Env conformational changes required for infection

Award Number: R01AI145687

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: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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