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

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

  • Nat Commun. 2024 Feb 14;15(1):1348. doi: 10.1038/s41467-024-45555-x.
Jinhee Kim 1,  Deepanwita Bose # 2,  Mariluz Araínga # 2,  Muhammad R Haque 3,  Christine M Fennessey 4,  Rachel A Caddell 5,  Yanique Thomas 3,  Douglas E Ferrell 2,  Syed Ali 2,  Emanuelle Grody 3 6,  Yogesh Goyal 3 6 7,  Claudia Cicala 8,  James Arthos 8,  Brandon F Keele 4,  Monica Vaccari 5 9,  Ramon Lorenzo-Redondo 1 10,  Thomas J Hope 3,  Francois Villinger 2,  Elena Martinelli 11
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
  • 3 Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 4 AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 5 Division of Immunology, Tulane National Primate Research Center, Covington, LA, USA.
  • 6 Center for Synthetic Biology, Northwestern University, Chicago, IL, USA.
  • 7 Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 8 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 9 Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA.
  • 10 Center for Pathogen Genomics and Microbial Evolution, Northwestern University Havey Institute for Global Health, Chicago, IL, USA.
  • 11 Department of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 38355731 DOI: 10.1038/s41467-024-45555-x
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.

Figures
Products