TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo
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 propertie...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45555-x |
| _version_ | 1797274138666074112 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jinhee Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:54:05Z |
| format | Article |
| id | doaj.art-fbe3b5ac6da84f6e995899f2ef2ce0bd |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:54:05Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-fbe3b5ac6da84f6e995899f2ef2ce0bd2024-03-05T19:32:46ZengNature PortfolioNature Communications2041-17232024-02-0115111710.1038/s41467-024-45555-xTGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivoJinhee Kim0Deepanwita Bose1Mariluz Araínga2Muhammad R. Haque3Christine M. Fennessey4Rachel A. Caddell5Yanique Thomas6Douglas E. Ferrell7Syed Ali8Emanuelle Grody9Yogesh Goyal10Claudia Cicala11James Arthos12Brandon F. Keele13Monica Vaccari14Ramon Lorenzo-Redondo15Thomas J. Hope16Francois Villinger17Elena Martinelli18Department of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern UniversityNew Iberia Research Center, University of Louisiana at LafayetteNew Iberia Research Center, University of Louisiana at LafayetteCell and Developmental Biology, Feinberg School of Medicine, Northwestern UniversityAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer ResearchDivision of Immunology, Tulane National Primate Research CenterCell and Developmental Biology, Feinberg School of Medicine, Northwestern UniversityNew Iberia Research Center, University of Louisiana at LafayetteNew Iberia Research Center, University of Louisiana at LafayetteCell and Developmental Biology, Feinberg School of Medicine, Northwestern UniversityCell and Developmental Biology, Feinberg School of Medicine, Northwestern UniversityLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer ResearchDivision of Immunology, Tulane National Primate Research CenterDepartment of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern UniversityCell and Developmental Biology, Feinberg School of Medicine, Northwestern UniversityNew Iberia Research Center, University of Louisiana at LafayetteDepartment of Medicine, Division of Infectious Diseases, Feinberg School of Medicine, Northwestern UniversityAbstract 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.https://doi.org/10.1038/s41467-024-45555-x |
| spellingShingle | 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 TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo Nature Communications |
| title | TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo |
| title_full | TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo |
| title_fullStr | TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo |
| title_full_unstemmed | TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo |
| title_short | TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo |
| title_sort | tgf β blockade drives a transitional effector phenotype in t cells reversing siv latency and decreasing siv reservoirs in vivo |
| url | https://doi.org/10.1038/s41467-024-45555-x |
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