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Relevance of serum mannosidase resistance to the specificity of oligomannose-targeting antibodies

Award Number: R21AI157317
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The glycans that decorate the HIV envelope glycoprotein spike (Env) are categorized nominally as ‘self’ antigens given that they are imparted by the mammalian cell’s glycosylation machinery. However, glycans of the oligomannose-type found on gp120 are mostly clustered into a patch, creating a ‘non-self’ architecture. This oligomannose patch is vulnerable to recognition by anti-HIV broadly neutralizing antibodies (bnAbs). Given the potency and breadth of bnAbs to the oligomannose patch, there is great interest in developing immunization strategies to elicit similar bnAbs. This project aims to fill a gap in understanding barriers to the elicitation of oligomannose-specific bnAbs. We and others have recently reported on a soluble mannosidase found in mammalian serum that trims oligomannosides on glycoconjugates designed to elicit oligomannose-specific antibodies upon immunization. Such trimming would explain why immunizing with oligomannosidic glycoconjugates typically yields antibodies that bind well to substructures of oligomannose but that bind with substantially lower avidity to full-sized oligomannose as presented on Env; the latter typifies the binding manner of bnAbs that target the oligomannose patch. In this application, we propose to determine the extent to which serum mannosidase activity is relevant to the quality of oligomannose-specific antibody responses. Specifically, we intend to construct a mannosidase-resistant glycoside, thus representing the greatest possible resistance to mannosidase trimming, and determine the specificity of the ensuing antibody response compared to its mannosidase- sensitive opposite. The project will take advantage of our published work of a bacterially inspired mimic of oligomannose that, as a neoglycoconjugate, elicits modest levels of HIV-neutralizing antibodies. We will investigate antibody responses at the polyclonal serum level as well as the monoclonal level; the latter should reveal similarities, if any, between the elicited antibodies and existing bnAbs. In sum, we expect the results of this project to shed light on barriers to evoking antibodies with capacity to bind the highly vulnerable oligomannose patch on HIV Env. Although the difficulty in eliciting oligomannose-specific bnAbs is often assumed to stem from B cell tolerance, our preliminary studies provide evidence for serum mannosidase posing at least an additional hindrance.


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 = $171,731 )
2022	2022	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$171,731
														Subtotal = $171,731

Issue Date FY: 2021 ( Subtotal = $116,610 )
2021	2021	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	000	1	6/21/2021	NEW	$116,610
2021	2021	SIMON FRASER UNIVERSITY	8888 UNIVERSITY DR SUITE 1200	BURNABY	BC			CAN	Allergy and Infectious Diseases Research	001	1	6/29/2021	NEW	$0
														Subtotal = $116,610

Grand Total All Awards = $288,341

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Relevance of serum mannosidase resistance to the specificity of oligomannose-targeting antibodies

Award Number: R21AI157317

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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