Harnessing germinal center hypoxia to develop an effective HIV vaccine

Active Project Grant Awarded Last action

Award ID
F31AI200609
Recipient
Awarding agency
Obligated
$80,042

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Originally
Place of performance
Galveston, TX 77555, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
HIV continues to be a severe global problem with 39 million people living with HIV in 20221. Currently, there is no licensed vaccine against HIV. The discovery of broadly neutralizing antibodies (BNABS) in chronically infected HIV patients sparked hope that a vaccine is POSSIBLE2-4. A novel approach to vaccine design has been created called "germline targeting" (GT) which seeks to activate rare B cells present in the innate repertoire that have the potential to develop into bnab producing plasma CELLS5-8. This rare B cell population is activated by a GT immunogen and are recruited to germinal centers (GCS) within lymphoid organs where they compete in iterative cycles of mutation and selection to gain affinity against their cognate ANTIGEN9. Successful GC B cells can develop into memory B cells (MBCS) that can persist for prolonged times after DEVELOPMENT10-12. Upon reencounter with a cognate antigen, MBCS can reenter GCS to further mutate and gain AFFINITY10,11,13. This is a vital parameter of GT targeting immunizations as this paradigm may require multiple rounds of immunization to elicit key mutations to produce BNABS14,15. A promising class of bnab to target for induction by vaccination is VRC01. This class of antibody is targeted to the conserved CD4 binding site on the HIV envelope PROTEIN16 and has been demonstrated to neutralize up to 98% of known HIV ISOLATES17. To recruit VRC01-class bnab precursors to GCS, specifically modified HIV envelope protein constructs named engineered outer domain germline targeting (EOD-GT) have been DESIGNED6,7,18. These EOD-GT immunogens activate and amplify germline VRC01-class precursors in both pre-CLINICAL19-21 and clinical STUDIES22. While these studies validate the GT strategy and predictive power of pre-clinical models, they also reveal key bottlenecks. A major bottleneck is the number of responding VRC01-class GC B cells and MBCS. A method to overcoming these bottlenecks may be in utilization of conserved pathways within GCS. GCS have recently been characterized as hypoxic MICROENVIRONMENTS23-25, and two hypoxia-induced pathways have been implicated in GC physiology. The neuropilin-1 (NRP-1) RECEPTOR26 along with the adenosine receptor A2AR27,28 have both been seen in GC populations, but their role is not fully understood. In other models, both pathways have been to be IMMUNOSUPPRESSIVE27-35. We hypothesize that NRP-1 and A2AR restrict the expansion of VRC01-class precursors in the GC. We further hypothesize that inhibition of these pathways will amplify VRC01-class responses. To investigate this hypothesis, we will utilize VRC01-class B cell transfer systems with validated physiological precursor frequencies along with knock-out lines and inhibitors to define the impact NRP-1 and A2AR have on the GC. Through the completion of these proposed experiments, we will characterize their influence on GC B cell competition, rate of mutation, and development into MBCS. This proposal will also assess the feasibility of targeting these pathways pharmacologically to enhance the production of VRC01-class GC and MBCS.

Transactions

Action Obligated Date
Amendment $40,021
Amendment $0
Original award $40,021

Quick answers

Who received award F31AI200609?

F31AI200609 was awarded to University Of Texas Medical Branch At Galveston by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 5, 2026.

How much is award F31AI200609 worth?

$80,042 has been obligated on F31AI200609.

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