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Harnessing adaptive NK cell transfer to deplete viral reservoirs

Award Number: R01AI161816
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: 04/16/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Harnessing adaptive NK cell transfer to deplete viral reservoirs - PROJECT SUMMARY Natural killer (NK) cells provide an immediate defense against viruses and tumors by virtue of their ability to respond to infected or malignant cells without prior antigenic stimulation. This is accomplished through the integration of signals from activating and inhibitory NK cell receptors (aNKRs & iNKRs). In humans and other primate species, these include C-type lectin receptors, such as CD94/NKG2A and CD94/NKG2C, and the highly polymorphic killer-cell immunoglobulin-like receptors (KIRs), both of which interact with MHC class I ligands. These receptor-ligand interactions are fundamental to the ability of NK cells to differentiate healthy cells from unhealthy cells and provide a potential mechanism of specificity for the development of “NK cell memory”. NK cells can have a significant impact on HIV-1 infection. KIR and HLA class I polymorphisms have been identified that are associated with lower viral loads and slower courses of disease progression and certain NK cell subsets can kill HIV-infected cells in culture. Thus, NK cell-based therapies represent a promising approach for targeting HIV-infected cells and reducing the size of viral reservoirs. We hypothesize that viral peptides bound by the MHC class I ligands of aNKRs are critical to NK cell recognition and killing of HIV/SIV-infected cells and that the adoptive transfer of ex vivo activated NK cells in combination with latency reversal can deplete viral reservoirs in SIV-infected macaques on suppressive antiretroviral therapy (ART). In Aim 1, we will determine the contribution of viral peptides bound by MHC class I ligands of aNKRs to NK cell recognition of HIV- and SIV-infected cells. These studies will utilize high-throughput cellular assays to rapidly screen viral peptides for MHC class I interactions with aNKRs and to identify substitutions that disrupt these interactions. The corresponding changes will be introduced into HIV-1 and SIV to assess their impact on NK cell responses to virus-infected cells. In Aim 2, we will assess the capacity of ex vivo expanded NK cells in combination with latency reversal to deplete viral reservoirs in SIV-infected, ART-suppressed rhesus macaques. This aim will take advantage of barcoded SIV and a potent new latency reversal agent to compare with maximal sensitivity the ability of autologous versus allogeneic NK cell transfer to reduce the rate of viral reactivation after discontinuing ART. In Aim 3, we will test the hypothesis that the depletion of viral reservoirs by adaptive NK cell transfer can be enhanced by an Env-specific antibody with antibody-dependent cellular cytotoxicity against SIV-infected cells. This aim will use a similar approach as Aim 2 to determine the extent to which coupling NK cell effector function to the unparalleled specificity of antibodies can maximize reservoir depletion. These unprecedented studies will provide a better understanding of the role of viral peptides in NK cell recognition of HIV- and SIV-infected cells and an important proof-of-concept for the development of NK cell therapies to eradicate HIV-1 reservoirs in chronically infected individuals.


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 = $760,984 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	5	4/11/2025	NON-COMPETING CONTINUATION	$760,984
														Subtotal = $760,984

Issue Date FY: 2024 ( Subtotal = $760,984 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	4	3/22/2024	NON-COMPETING CONTINUATION	$760,984
														Subtotal = $760,984

Issue Date FY: 2023 ( Subtotal = $775,114 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	3	3/15/2023	NON-COMPETING CONTINUATION	$775,114
														Subtotal = $775,114

Issue Date FY: 2022 ( Subtotal = $751,016 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	2	3/25/2022	NON-COMPETING CONTINUATION	$751,016
														Subtotal = $751,016

Issue Date FY: 2021 ( Subtotal = $764,536 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	1	4/15/2021	NEW	$764,536
														Subtotal = $764,536

Grand Total All Awards = $3,812,634

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Harnessing adaptive NK cell transfer to deplete viral reservoirs

Award Number: R01AI161816

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: 04/16/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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