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HIV-1 envelope structure, stability and dynamics probed by saturation mutagenesis

Award Number: R01AI118366
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: 07/15/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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HIV-1 envelope structure, stability and dynamics probed by saturation mutagenesis - ¿ DESCRIPTION (provided by applicant): Despite considerable efforts for close to thirty years, we are still far from having an effective vaccine against HIV-1. Recent results of the RV144 efficacy trial have provided the first proof in humans that HIV infection can be diminished by vaccination and showed that the antibody response against the HIV-1 surface protein Env, contributes significantly to protection. A major hurdle to an HIV-1 vaccine is the availability of n immunogen that elicits broadly neutralizing antibodies. Lack of high resolution structural information for native, unliganded Env as well as its instability, flexibility, glycosylation and hgh sequence diversity are major contributors to this problem. An important recent development is the availability of medium resolution structures of a part of the Env ectodomain that reveal some details of gp120:gp41 interactions. However these lack some functionally important regions of the ectodomain, sidechain locations for the gp41 subunit, possess an additional disulfide bond and are complexed to antibody ligands. While some of these limitations may be overcome in future studies, it is unlikely that there will be a high resolution crystal structure of functional unliganded Env in the context of intact virus in the near future. The goals of this proposal are to apply saturation suppressor mutagenesis methodology in conjunction with appropriate infectivity screens, deep sequencing and protein labeling to obtain insight into the structure, stability and dynamics of intact Env in its native context on the viral surface. There are three specific Aims. I Aim 1 we will use saturation and saturation-suppressor mutagenesis to validate and extend structural information recently derived from gp140 trimers to full length Env on virions, and to identify trimer stabilizing mutations. Increased structural information is vital to understanding Env function and the mechanism of viral entry. Improving the stability and rigidity of unliganded trimers should improve the elicitation of neutralizing antibodies when such molecules or their derivatives are used as immunogens. In Aim2 we will probe Env dynamics using Cys labeling of env on intact virions. Little is known at the molecular level about the flexibility and stability o the native HIV-1 trimer on virions. Such information is also vital for designing better immunogens and for understanding viral entry. In Aim3 we will design fragment models of the gp120:gp41 interface based on structural input from existing structures and mutagenesis data. Stabilizing mutations derived from these studies will be incorporated into soluble gp120:gp41 complexes, which are potential immunogens. These simplified interface models will also be used to design inhibitors of viral entry.


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: 2022 ( Subtotal = -$15 )
2022	2019	INDIAN INSTITUTE OF SCIENCE	C V RAMAN ROAD, DEVASANDRA LAYOUT, (BANGALORE) URBAN,	BENGALURU				IND	Allergy and Infectious Diseases Research	000	5	1/21/2022	NON-COMPETING CONTINUATION	-$15
														Subtotal = -$15

Issue Date FY: 2019 ( Subtotal = $121,500 )
2019	2019	INDIAN INSTITUTE OF SCIENCE	C V RAMAN AVENUTE, SCIENCE INSTITUTE POST OFFICE,	BANGALORE	KARNATAKA	560012		IND	Allergy and Infectious Diseases Research	000	5	6/24/2019	NON-COMPETING CONTINUATION	$121,500
														Subtotal = $121,500

Issue Date FY: 2018 ( Subtotal = $120,700 )
2018	2018	INDIAN INSTITUTE OF SCIENCE	C V RAMAN AVENUTE, SCIENCE INSTITUTE POST OFFICE,	BANGALORE	KARNATAKA	560012		IND	Allergy and Infectious Diseases Research	000	4	6/13/2018	NON-COMPETING CONTINUATION	$120,700
														Subtotal = $120,700

Issue Date FY: 2017 ( Subtotal = $121,500 )
2017	2017	INDIAN INSTITUTE OF SCIENCE	C V RAMAN AVENUTE, SCIENCE INSTITUTE POST OFFICE,	BANGALORE	KARNATAKA	560012		IND	Allergy and Infectious Diseases Research	000	3	6/1/2017	NON-COMPETING CONTINUATION	$121,500
														Subtotal = $121,500

Issue Date FY: 2016 ( Subtotal = $121,500 )
2016	2016	INDIAN INSTITUTE OF SCIENCE	REGISTRAR	BANGALORE				IND	Allergy and Infectious Diseases Research	000	2	6/29/2016	NON-COMPETING CONTINUATION	$121,500
														Subtotal = $121,500

Issue Date FY: 2015 ( Subtotal = $121,500 )
2015	2015	INDIAN INSTITUTE OF SCIENCE	REGISTRAR	BANGALORE				IND	Allergy and Infectious Diseases Research	000	1	7/15/2015	NEW	$121,500
														Subtotal = $121,500

Grand Total All Awards = $606,685

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HIV-1 envelope structure, stability and dynamics probed by saturation mutagenesis

Award Number: R01AI118366

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: 07/15/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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