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

• Published in: Nature communications Vol. 15; no. 1; pp. 1348 - 17
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/21; 13/31; 38/22; 38/91; 45/77; 45/88; 45/90; 59/78; 631/250/251; 631/250/255/1901; 64; 692/308/575; 82/79; 96; Animals; Antiretroviral therapy; Biocompatibility; CD4-Positive T-Lymphocytes; Clinical trials; Cytometry; Effector cells; Female; Genotype & phenotype; Hepatocyte nuclear factor 1; HIV; Human immunodeficiency virus; Humanities and Social Sciences; Immune system; Inflammation; Inhibitors; Latency; Leukocytes, Mononuclear; Lymph nodes; Lymphocytes; Lymphocytes T; multidisciplinary; Peripheral blood mononuclear cells; Phenotypes; Science; Science (multidisciplinary); Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Toxicity; Transforming Growth Factor beta; Transforming growth factor-b; Viral Load; Virus Replication
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45555-x

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 64 Cu-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.