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.