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A new strategy to eliminate HIV-1-infected cells by unlocking the Env trimer

Award Number: R01AI174908
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: 08/07/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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A new strategy to eliminate HIV-1-infected cells by unlocking the Env trimer - Project Abstract The difficulty in eliminating HIV-1-infected cells is a major roadblock in eradication strategies. This is due to several factors which includes the occlusion of vulnerable HIV-1 envelope glycoprotein (Env) epitopes that can be recognized by antibodies (Abs) capable of potent Fc-effector functions such as Antibody-Dependent Cellular Cytotoxicity (ADCC). With this application we propose to engineer Abs specific for highly conserved CD4 induced (CD4i) Env epitopes to overcome these obstacles and facilitate the elimination of HIV-1 infected cells via ADCC. Accordingly, our central hypothesis is that CD4i therapeutic Abs (tAbs) will be capable of more effective elimination of infected primary CD4+ cells in the presence of HIV+ plasma than the best in class broadly neutralizing Abs (bnAbs) and can thus be developed into a new family of tAb that will be effective in decreasing and ultimately eliminating the viral reservoir in people living with HIV-1 (PLWH). The proposed research builds upon our successful development of new Ab-CD4 hybrids from weakly neutralizing or CD4i Abs specific for the coreceptor binding site (CoRBS) or highly conserved, non-neutralizing gp120 inner domain Cluster A region. Our lead CoRBS and Cluster A Ab-CD4 hybrids efficiently eliminate cells infected with primary HIV-1 isolates both in vitro and ex vivo, demonstrating that they can circumvent the occlusion of epitopes on infected cells and virions. Furthermore, they are also able to harness the ADCC activity of Abs present in HIV+ plasma, further enhancing ADCC. Finally, an anti-Cluster A Ab-CD4 hybrid (e.g., A32-CD4) also inhibited viral rebound in hu-mice and led to a significant reduction in integrated HIV DNA in an Fc-dependent manner. In the proposed project, we will engineer Ab-CD4s of other CD4i specificities and also replace the CD4 moiety with potent small molecule CD4 mimetic compounds (CD4mc). These next generation Ab-CD4mc conjugates will efficiently sensitize HIV-1 infected cells to ADCC-mediated killing, providing a new tool to decrease the HIV-1-infected cell reservoir in PLWH. Aim 1 is designed to prepare Ab-CD4 hybrids of other CD4i specificities including the Cluster A, C11- like and the gp41 Principal Immunodominant regions. Aim 2 will develop Ab-CD4mc conjugates in which the CD4 moiety of the Ab-CD4 will be replaced by a new generation of small compound CD4mcs including BNM-III- 170 and/or more active CD4mcs. The CD4mc will be attached to the Ab through a PEG linker using a novel tRNA suppressor system. Ab-CD4/CD4mcs will be evaluated in vitro and ex-vivo for their ability to neutralize primary viruses and eliminate HIV-1-infected cells alone or synergistically with HIV+ plasma, both in vitro and ex-vivo. Aim 3 will test the capacity of the best engineered variants to reduce the size of viral reservoir in humanized mice engrafted with PBMC from PLWH. This final aim will evaluate the capacity of the most promising engineered variants to eliminate infected cells in vivo and delay viral rebound. Overall, the project will generate a new family of potent tAbs able to eliminate HIV-1 infected cells to add new weapons to the growing arsenal aimed at achieving a functional cure of HIV-1.


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 = $690,610 )
2025	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	8/12/2025	NON-COMPETING CONTINUATION	$690,610
														Subtotal = $690,610

Issue Date FY: 2024 ( Subtotal = $699,744 )
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	2	8/13/2024	NON-COMPETING CONTINUATION	$45,042
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	7/25/2024	NON-COMPETING CONTINUATION	$654,702
														Subtotal = $699,744

Issue Date FY: 2023 ( Subtotal = $716,299 )
2023	2023	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	8/7/2023	NEW	$716,299
2023	2023	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	1	8/14/2023	NEW	$0
														Subtotal = $716,299

Grand Total All Awards = $2,106,653

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A new strategy to eliminate HIV-1-infected cells by unlocking the Env trimer

Award Number: R01AI174908

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: 08/07/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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