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

Jinhee Kim, Deepanwita Bose, Mariluz Araínga, Muhammad R. Haque, Christine M. Fennessey, Rachel A. Caddell, Yanique Thomas, Douglas E. Ferrell, Syed Ali, Emanuelle Grody, Yogesh Goyal, Claudia Cicala, James Arthos, Brandon F. Keele, Monica Vaccari, Ramon Lorenzo-Redondo, Thomas J. Hope, Francois Villinger, Elena Martinelli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Article number1348
JournalNature communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

Fingerprint

Dive into the research topics of 'TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo'. Together they form a unique fingerprint.

Cite this