Relevance of serum mannosidase resistance to the specificity of oligomannose-targeting antibodies
Ended Project Grant Awarded Last action
- Award ID
- R21AI157317
- Recipient
-
Simon Fraser University UEI Q8FRNDEN4VA3
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $693,292
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date
- Originally
- Funding
-
- $576,682.00 Federal
- $116,610.00 Non-federal
- Place of performance
- 2323 Riverside Dr., Ottawa, ON K1H 1A1, Canada
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $171,731 | $0 | |
| Amendment | $171,731 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $116,610 | $0 | |
| Original award | $116,610 | $116,610 |
Quick answers
Who received award R21AI157317?
R21AI157317 was awarded to Simon Fraser University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on June 22, 2021.
How much is award R21AI157317 worth?
$693,292 has been obligated on R21AI157317: $576,682 in federal funding and $116,610 in non-federal funding.
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