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Reversing effector-to-memory transition at ARTi to impact the HIV reservoir towards ART-free control

Award Number: R01AI192331
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: 09/01/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Reversing effector-to-memory transition at ARTi to impact the HIV reservoir towards ART-free control - HIV persistence during ART is primarily due to the establishment of long-lived viral reservoirs in resting immune cells and mucosal and lymphoid tissues. Recently, we showed that blocking TGFβ in a non-human primate model (NHP) of mucosal SIV infection leads to enhanced T cell differentiation toward effectors, which in turn leads to SIV latency reversal. TGFβ, the master regulator of tissue immunity, is increased in HIV-1/SIV infection and its levels remain elevated with ART. We found an increased TGFβ signature at ART initiation (ARTi) including an increase in quiescent/resting memory T cells which parallel a decrease in effectors with waning immune responses and decreasing viral loads. Herein, we propose to use TGFβ blockade during ART initiation to reverse the resting/quiescent status of T cells and support viral transcription while ART blocks new infection. We hypothesize that this will decrease latency establishment and reduce the levels of the already established reservoir especially when TGFβ blockade is used in combination with a broadly neutralizing antibody (bNAb). As proof-of-principle we will test this combination in a non-human model of SHIV-AD8 infection with 4 groups of monkeys: 1) TGFβ blockade with galunisertib, 2) HIV-bNAbs, 3) Galunisertib+bNAbs, 4) Isotype control. Moreover, in order to investigate whether galunisertib’ s ability to stimulate the immune system and enhance the vaccinal effect of the bNAb, we will label HIV-bNAbs with Cy5 and follow their dynamics in vivo. PET/CT-guided collection of tissue areas of viral reactivation will allow us to study the impact of bNAbs in tissues and determine whether galunisertib increases their ADCC activity. Overall, we expect to be able to reduce viral reservoir and stimulate immune responses so that at the end of ~1 year of ART, viral rebound upon ART interruption will be delayed or controlled.


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: 2026 ( Subtotal = $1,031,799 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	8/13/2026	NON-COMPETING CONTINUATION	$1,031,799
														Subtotal = $1,031,799

Issue Date FY: 2025 ( Subtotal = $1,016,951 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	8/29/2025	NEW	$1,016,951
														Subtotal = $1,016,951

Grand Total All Awards = $2,048,750

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Reversing effector-to-memory transition at ARTi to impact the HIV reservoir towards ART-free control

Award Number: R01AI192331

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: 09/01/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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