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Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1

Award Number: U01AI169767
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/11/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1 - Modified Project Summary/Abstract Section: Advances in B cell biology and molecular virology have enabled the discovery, characterization, and commercial development of several classes of broadly neutralizing antibodies (bnAbs), with applications for prevention, treatment, and cure of HIV disease are under study. Yet, virus resistance remains the central vulnerability of effective bnAb use. This application proposes to address the problem of bNAb escape by rationally selecting combination bNAb therapy that limits virus escape. We propose to apply lessons from the successful development of combination antiretrovial therapy (cART), whereby bidirectional phenotypic antagonism was exploited. Our multidisciplinary team has secured plasma virus or virus sequences from recent or ongoing prevention and treatment studies of VRC01-class CD4 binding site (CD4bs)-targeting monotherapy, as well as combination therapy with V3 glycan-targeting (Table 1). We will leverage these unique samples to map the in vivo escape pathways of virus replicating in the presence of sub-suppressive levels of these clinically relevant bNAbs (Aim 1). Using the evolving escape variants, we will identify putative complementary bNAbs with maintained or inverse antibody sensitivities from rationally designed panels of candidate bNAbs (Aim 1). We will then characterize the autologous neutralizing antibody (anAb) response in the treatment cohorts, to determine the capacity of anAbs to impede virus escape from administered bNAbs (Aim 2). Finally, we will test the most promising complementary bNAbs to restrict virus escape in cell culture, in vivo in humanized mice and a validated barcoded TF SHIV/NHP model (Aim 3). Our scientific premise is that in vivo mapping of virus escape from bNAbs, identification of complementary bNAbs, defining the role of autologous antibodies, and rigorous in vivo testing in an authentic NHP model will elucidate basic mechanisms of virus resistance to bNAbs and inform more effective use of bNAbs across the HIV prevention, treatment and cure fields. If accomplished we will (i) have defined the sensitivities of escaped viruses from clinical trials to alternate bNAbs, (ii) identified bNAbs that cannot mutually escape using the same pathway, (iii) defined the role of anAbs in bnAb escape and (iv) tested the ability of complementary bnAbs to improve therapy in an authentic NHP model.


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: 2026 ( Subtotal = $1,721,127 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	4/6/2026	NON-COMPETING CONTINUATION	$1,721,127
														Subtotal = $1,721,127

Issue Date FY: 2025 ( Subtotal = $1,849,302 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	6/13/2025	NON-COMPETING CONTINUATION	$1,849,302
														Subtotal = $1,849,302

Issue Date FY: 2024 ( Subtotal = $1,927,304 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	3	4/15/2024	NON-COMPETING CONTINUATION	$173,974
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	2/15/2024	NON-COMPETING CONTINUATION	$1,753,330
														Subtotal = $1,927,304

Issue Date FY: 2023 ( Subtotal = $1,427,237 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	2	3/9/2023	NON-COMPETING CONTINUATION	$1,427,237
2023	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	3/2/2023	NEW	$0
														Subtotal = $1,427,237

Issue Date FY: 2022 ( Subtotal = $1,481,429 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	4/11/2022	NEW	$1,481,429
														Subtotal = $1,481,429

Grand Total All Awards = $8,406,399

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Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1

Award Number: U01AI169767

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/11/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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