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 language | English (US) |
|---|---|
| Article number | 1348 |
| Journal | Nature communications |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
General: We acknowledge the helpful staff at the New Iberia Research Center as well as the help of Dr. Suchitra Swaminathan and the rest of the staff of the Flow Cytometry Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. Moreover, we thank the staff of the NUseq Core at Northwestern, and in particular Dr. Ching Man Wai and Matthew Schipma for the help with RNAseq data. Finally, we thank Dr. Lifson and the Leidos staff for viral load measurements as well as Dr. Laird at Accelevir for providing SIV-TILDA results in a timely manner. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Funding: This project has been funded by National Institutes of Health grant R56AI157822 and R01AI-176599 to Dr. Martinelli, the resource for NHP immune reagents to Dr. Villinger (R24 OD010947) for probe productions and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I. The Lurie Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA060553. General: We acknowledge the helpful staff at the New Iberia Research Center as well as the help of Dr. Suchitra Swaminathan and the rest of the staff of the Flow Cytometry Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. Moreover, we thank the staff of the NUseq Core at Northwestern, and in particular Dr. Ching Man Wai and Matthew Schipma for the help with RNAseq data. Finally, we thank Dr. Lifson and the Leidos staff for viral load measurements as well as Dr. Laird at Accelevir for providing SIV-TILDA results in a timely manner. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Funding: This project has been funded by National Institutes of Health grant R56AI157822 and R01AI-176599 to Dr. Martinelli, the resource for NHP immune reagents to Dr. Villinger (R24 OD010947) for probe productions and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I. The Lurie Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA060553.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
