Abstract
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-β blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on ART were treated with four 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption(ATI). All macaques rebounded between week 2 and 6 post-ATI, but one did not. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with 64Cu-DOTA-F(ab’)2-p7D3-probe. A 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 characterized by a progressive downregulation in TCF1.
In summary, we demonstrated that galunisertib, a clinical stage TGF-β inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity.
One-sentence summary TGF-β blockade drives an effector phenotype in immune cells leading to SIV latency reversal and enhanced immune responses in vivo.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Change the SUVtot to SUVmean in Fig2 and add analysis of PET/CT data including gating strategy. This should help with the interpretation of the PET/CT images shown, but does not alter the conclusions in the manuscript
