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Revealing the Biophysics of the Germinal Center Microenvironment

Award Number: DP2AI154410
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: 12/22/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Revealing the Biophysics of the Germinal Center Microenvironment - Abstract Is an HIV vaccine possible? Vaccines are one of the most successful public health interventions over the past century. Nearly all vaccines work by induction of protective antibodies. However, our understanding of the cellular dynamics of immune responses to vaccines, particularly the biology surrounding B cell competition within germinal centers (GC) to complex vaccine antigens is limited. This lack of understanding of fundamental B cell biology has contributed to the inability to develop an effective HIV vaccine. Promisingly, a small population of HIV+ individuals have developed broadly neutralizing antibodies (bnAbs), giving renewed hope that an HIV vaccine is possible. Recent work has found that many HIV negative healthy human donors have VRC01-class bnAb precursor B cells. However, work from these studies revealed that these potential bnAb precursor B cells are found at an unusually rare frequency. This suggested that following immunization these B cells may be outcompeted by more frequent non-neutralizing B cells. To answer immunological questions surrounding this problem, I developed a model system utilizing mice containing human genes for the germline-reverted VRC01 bnAb (VRC01gHL). Through this B cell transfer model, we found that antigen affinity, avidity, and precursor frequency all played interdependent roles in competitive success of rare VRC01gHL B cells in GCs. Critically, we found that rare VRC01gHL B cells with physiological affinities could be primed to successfully compete within GCs. However, these responses were limited to specific “GC” islands suggesting B cell competition to seed individual GCs is critical in addition to competition within the GC. Taken together, these observations suggest that B cell immunodominance in the GC microenvironment (GCME) is a major obstacle to overcome in developing a successful HIV vaccine. However, there are significant knowledge gaps pertaining to the physiological conditions in which B cells compete to enter GCs, and compete within the GCME. To start, what do we know about the biophysical and metabolic characteristics of the GCME? We hypothesized and found that GCs form a hypoxic microenvironment. I hypothesize that other biophysical constraints may be acting to control GC selection events as many pathways have been shown to be both active in hypoxic tumor microenvironments (TMEs) and in the hypoxic GCME. I hypothesize that in further correlation with TMEs, the GCME may contain high lactate levels, induce multiple metabolic GPCRs, reduced pH, increased temperature, and cellular pressure. I posit that these biophysical parameters of the GC can and do influence B cell selection events to complex antigens. In this DP2 proposal I will investigate the nature of the extracellular milieu of the GCME through multi- photon targeted direct measurements and define the biophysical constraints that limit the success of VRC01- class B cell responses. We will then apply what we learn from studying the GCME to manipulate B cell immunodominance in the GCME to favor competitive selection of VRC01-class B cells.


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 = $480,000 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	4	12/18/2024	NON-COMPETING CONTINUATION	$14,400
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	4	11/22/2024	NON-COMPETING CONTINUATION	$465,600
														Subtotal = $480,000

Issue Date FY: 2024 ( Subtotal = $480,000 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	3	5/16/2024	NON-COMPETING CONTINUATION	$47,999
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	3	11/9/2023	NON-COMPETING CONTINUATION	$432,001
														Subtotal = $480,000

Issue Date FY: 2023 ( Subtotal = $480,000 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	11/10/2022	NON-COMPETING CONTINUATION	$480,000
														Subtotal = $480,000

Issue Date FY: 2022 ( Subtotal = $446,400 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	1	7/28/2022	NEW	$0
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	12/22/2021	NEW	$446,400
														Subtotal = $446,400

Grand Total All Awards = $1,886,400

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Revealing the Biophysics of the Germinal Center Microenvironment

Award Number: DP2AI154410

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: 12/22/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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