TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo.

Autor: Kim, Jinhee, Bose, Deepanwita, Araínga, Mariluz, Haque, Muhammad R., Fennessey, Christine M., Caddell, Rachel A., Thomas, Yanique, Ferrell, Douglas E., Ali, Syed, Grody, Emanuelle, Goyal, Yogesh, Cicala, Claudia, Arthos, James, Keele, Brandon F., Vaccari, Monica, Lorenzo-Redondo, Ramon, Hope, Thomas J., Villinger, Francois, Martinelli, Elena
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Zdroj: Nature Communications; 2/14/2024, Vol. 15 Issue 1, p1-17, 17p
Abstrakt: 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 anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirm the latency reversal properties of in vivo TGF-β blockade, decrease viral reservoirs and stimulate immune responses. Treatment of eight female, SIV-infected macaques on ART with four 2-weeks cycles of galunisertib leads to viral reactivation as indicated by plasma viral load and immunoPET/CT with a 64Cu-DOTA-F(ab')2-p7D3-probe. Post-galunisertib, lymph nodes, gut and PBMC exhibit lower cell-associated (CA-)SIV DNA and lower intact pro-virus (PBMC). Galunisertib does not lead to systemic increase in inflammatory cytokines. High-dimensional cytometry, bulk, and single-cell (sc)RNAseq reveal a galunisertib-driven shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1. In summary, we demonstrate 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. Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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