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Characterizing HIV-1 Env conformations susceptible to attack by non-neutralizing antibodies

Award Number: R01AI150322
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: 12/23/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Characterizing HIV-1 Env conformations susceptible to attack by non-neutralizing antibodies - SUMMARY While current antiretroviral therapies (ART) are able to control HIV replication, they are unable to fully restore health or a normal immune status. ART-treated individuals still experience several co-morbidities including increased cardiovascular disease, bone disorders, and cognitive impairment. Most importantly, therapy interruption leads to the re-emergence of viral replication and progression to AIDS. Therefore, new approaches aimed at eradicating or functionally curing HIV infection are desperately needed. An under-studied strategy to eliminate latently infected cells after viral reactivation relies on the ability of immune cells to mediate antibody- dependent cellular cytotoxicity (ADCC). The RV144 HIV-1 vaccine trial in Thailand elicited a 31.2% protective efficacy, making it the first vaccine trial with any level of success in generating a protective response. Subsequent analyses indicated that this modest protection was correlated with the generation of antibodies (Abs) with high ADCC activity, in the presence of low plasma IgA Env-specific Abs. This suggests that ADCC may have contributed to the protection observed in the RV144 trial. But key unanswered questions exist that prevent researchers from specifically triggering the ADCC response with novel treatments or immunogens: Why did the RV144 trial generate such a strong ADCC response? What about the CRF01_AE subtype of HIV-1, which predominates the Thai AIDS epidemic, might make it especially susceptible to ADCC? Does Env conformation affect ADCC responses? Answering these questions will prove crucial to the design of improved strategies to eliminate HIV-1-infected cells. The long-term goal of the research described in this proposal is to inform the development of new strategies for utilizing the ADCC response to eradicate the HIV-1 infection. To achieve this goal, we will begin by describing in molecular detail the Env conformations that are susceptible to attack by Abs that induce ADCC, and to determine the structural elements of Env from distinct HIV-1 strains that mediate transition to these conformations. Our central hypothesis is that Env has intrinsic access to downstream conformations that are recognized by easily-elicited non-neutralizing Abs. Some of which, like the anti-cluster A Abs, have potent ADCC activity. In support of this hypothesis, we recently demonstrated using Ab-binding assays, cryo-electron microscopy (Cryo-EM), and single-molecule Förster resonance energy transfer (smFRET) imaging that HIV-1 Env can adopt a conformation that is sensitive to attack by Abs that have potent ADCC activity (State 2A). The rationale underlying this proposal is that characterization of the structure of Env State 2A, as wells as other conformations recognized by non-neutralizing Abs, and the elements that mediate stabilization of these conformations will inform new strategies to eliminate the latent HIV reservoir.


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: 2024 ( Subtotal = $541,156 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	5	11/15/2023	NON-COMPETING CONTINUATION	$487,042
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	001	5	5/16/2024	NON-COMPETING CONTINUATION	$54,114
														Subtotal = $541,156

Issue Date FY: 2023 ( Subtotal = $538,456 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	4	11/8/2022	NON-COMPETING CONTINUATION	$538,456
														Subtotal = $538,456

Issue Date FY: 2022 ( Subtotal = $540,616 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	3	11/1/2021	NON-COMPETING CONTINUATION	$540,616
														Subtotal = $540,616

Issue Date FY: 2021 ( Subtotal = $536,296 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	2	11/6/2020	NON-COMPETING CONTINUATION	$536,296
														Subtotal = $536,296

Issue Date FY: 2020 ( Subtotal = $588,001 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Allergy and Infectious Diseases Research	000	1	12/23/2019	NEW	$588,001
														Subtotal = $588,001

Grand Total All Awards = $2,744,525

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Characterizing HIV-1 Env conformations susceptible to attack by non-neutralizing antibodies

Award Number: R01AI150322

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: 12/23/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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