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Defining the mechanisms of HIV resistance to bNAbs in humans

Award Number: U01AI169385
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: 07/05/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Defining the mechanisms of HIV resistance to bNAbs in humans - PROJECT SUMMARY Combination antiretroviral therapy (ART) revolutionized the treatment and prevention of HIV-1 infection. However, ART does not eradicate established infection and worldwide HIV-1 incidence rates remain high and have been declining slowly. Thus, the search for novel preventive and therapeutic interventions remains a high priority. In recent years, broadly neutralizing antibodies (bNAbs) emerged as a long-acting alternative to daily ART and as a promising strategy to achieve long-term treatment-free HIV-1 control. bNAbs differ from ART in that they engage the host immune system by virtue of their Fc effector domains and therefore have the potential to mediate killing of infected cells and modulate or enhance HIV-specific immune responses. However, bNAbs are vulnerable to escape by HIV-1 variants. During HIV-1 infection, antibody responses co-evolve with a large population of rapidly mutating viruses, such that variants that are resistant to individual antibodies are frequently encountered. Consistent with this high level of diversity, several clinical studies have demonstrated that bNAb monotherapy leads to transient declines in viremia with rapid selection of bNAb-resistant viral strains. In contrast, a combination of two bNAbs targeting non-overlapping Env epitopes maintained viral suppression in participants harboring antibody sensitive viruses who had achieved viral suppression with ART and subsequently received repeated doses of bNAbs during ART interruption. These early studies demonstrate the potential therapeutic application of bNAbs but also highlight the need to better understand viral escape pathways leading to bNAb resistance. Although resistance to some bNAbs (i.e. anti-V3 loop) is predicated on known features of Env, the determinants of resistance are poorly defined for other bNAbs and for combinations of bNAbs. The overarching goals of this proposal are to understand the diversity of pathways leading to bNAb escape and use this information to guide the design of more effective optimized bNAb combinations that prevent emergence of resistant variants. This proposal has four interrelated aims directed at accomplishing these goals: (1) Determine the sequence elements that lead to viral resistance to bNAb administration in humans using newly developed next generation deep sequencing methods; (2) Systematically map all possible viable bNAb resistance mutations to identify mechanisms of escape across viral strains and subtypes by producing and testing complete libraries of Env mutants; (3) Determine the nature of clinically relevant bNAb-resistant HIV-1 variants that can be selected in cell culture in the presence or absence of autologous serum; (4) Develop computational models that define mechanisms of HIV-1 bNAb resistance by integrating the sequence information obtained from Aims 1-3.


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 = $1,569,774 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	4/18/2025	NON-COMPETING CONTINUATION	$1,569,774
														Subtotal = $1,569,774

Issue Date FY: 2024 ( Subtotal = $1,569,774 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	4/15/2024	NON-COMPETING CONTINUATION	$1,569,774
														Subtotal = $1,569,774

Issue Date FY: 2023 ( Subtotal = $1,569,774 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	4/5/2023	NON-COMPETING CONTINUATION	$1,569,774
														Subtotal = $1,569,774

Issue Date FY: 2022 ( Subtotal = $1,569,774 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	7/5/2022	NEW	$1,569,774
														Subtotal = $1,569,774

Grand Total All Awards = $6,279,096

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Defining the mechanisms of HIV resistance to bNAbs in humans

Award Number: U01AI169385

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: 07/05/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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