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Activating Latently Infected Cells Using Specific Antigens Including Those of HIV-1

Award Number: R33AI116194
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: 01/19/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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Activating Latently Infected Cells Using Specific Antigens Including Those of HIV-1 - DESCRIPTION (provided by applicant): HIV-1 is not cured despite therapy that reduces viral replication to nearly undetectable levels, because reservoirs of virus persist in the host. These reservoirs persist because the virus establishes latent infection, primarily in CD4-positive memory T cells. These cells reactivate at a low but relatively constant frequency, leading to recrudescent viremia within 1-2 weeks after drug-therapy is stopped. These reactivation events are presumably stochastic, but we hypothesize that they can be induced by the specific antigens to which the cells are programmed to respond. Here, we propose to test this hypothesis and define those antigens, toward the goal of developing new approaches to the reactivation of latently infected cells that are potent yet selective. During the R21 phase, Specific Aim 1 will determine whether latency can be reversed in cells from infected patients by stimulation with HIV-1 antigens. HIV-infection favors cells that respond immunologically to the virus itself, so we hypothesize that many if not most latently infected CD4-positive memory T cells will respond to HIV antigens. To test this, we will measure the reactivation of viral gene expression ex vivo in latently infected cells from HIV-infected persons, first using peptide pools corresponding to HIV-1 proteins, and second, using replication-defective but authentic whole virions, which we can produce in large amounts, as antigens. By comparing the reactivation by HIV-1 antigens to that of maximal T cell stimulation, we will determine how effective specific antigenic stimulation might be. Specific Aim 2 will determine whether latency can be reversed in infected CD4-positive T cells by antigens other than HIV-1 to which the patient likely has immunologic memory. Specific Aim 3 will compare the abilities of these antigens to reverse latency with their abilities to stimulate the overall CD4 T cell population; this tests the hypotheis that latency is differentially established in cells with different antigen-specificities, and in particular that it is established preferentially in HIV-specific cells. The identification of antigns, either from HIV or other pathogens, that activate a substantial fraction of latently infected cells from patients ex vivo is the milestone for progression to the R33 phase. The R33 phase will provide in depth study of the potential of the antigens tested above to be used in therapeutic "vaccinations", toward the goal of immunologically reactivating and eliminating latently infected cells. Specific Aim 4 will determine the broad applicability of the approach by optimizing antigenic mixtures and applying them to a larger cohort of patient cells. Specific Aim 5 will determine whether latently infected cells reactivated by specific antigens die spontaneously or can be killed by various aspects of innate and acquired cytotoxic immunity. These studies should facilitate the design of clinical trials, the goal of which would be to reactivate latently infected cells by provision of antigens to which the cells are programmed to respond, and to promote cytotoxic immunity that recognizes and kills those cells.


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 = -$10,146 )
2024	2020	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	4/22/2024	NON-COMPETING CONTINUATION	-$10,146
														Subtotal = -$10,146

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	8/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $399,707 )
2020	2020	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	7/17/2020	NON-COMPETING CONTINUATION	$399,707
														Subtotal = $399,707

Issue Date FY: 2019 ( Subtotal = $432,482 )
2019	2019	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	4	7/26/2019	NON-COMPETING CONTINUATION	$399,275
2019	2018	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	2/21/2019	EXTENSION WITH OR WITHOUT FUNDS	$33,207
														Subtotal = $432,482

Issue Date FY: 2018 ( Subtotal = $396,139 )
2018	2018	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	7/13/2018	EXTENSION WITH OR WITHOUT FUNDS	$396,139
														Subtotal = $396,139

Grand Total All Awards = $1,218,182

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Activating Latently Infected Cells Using Specific Antigens Including Those of HIV-1

Award Number: R33AI116194

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: 01/19/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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