TGF-beta blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo [RNA-seq]
HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties of in vivo TGF-beta blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on suppressive ART were treated with 4 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption(ATI). One macaque did not rebound, while the remaining rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with the 64Cu-DOTA-F(ab')2-p7D3-probe. Half to 1 Log decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk and single-cell RNAseq revealed a shift toward an effector phenotype in T and NK cells. Overall design: To understand early and later effect of galunisertib in the context of SIV infection, we performed bulk RNAseq of PBMCs isolated from before cycle 1 (24hrs) and 1hrs after the first dose of galunisertib or after the last dose of cycle 1 We also performed bulk RNAseq of rectal biopsy specimens collected before cycle 1 (24hrs) and after the last dose of cycle 1. 7 Macaques, 3 time points for PBMCs, 2 time points for Rectal Biopsies