التفاصيل البيبلوغرافية
| العنوان: |
TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo. |
| المؤلفون: |
Kime J, Bose D, Arainga M, Haque MR, Fennessey CM, Caddell RA, Thomas Y, Ferrell DE, Ali S, Grody E, Goyal Y, Cicala C, Arthos J, Keele BF, Vaccari M, Lorenzo-Redondo R, Hope TJ, Villinger FJ, Marinelli E |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 15. Date of Electronic Publication: 2023 Dec 15. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
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 the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties of in vivo TGF-β blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on suppressive ART were treated with 4 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption(ATI). One macaque did not rebound, while the remaining rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with the 64Cu-DOTA-F(ab')2-p7D3-probe. Half to 1 Log decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk and single-cell RNAseq revealed a shift toward an effector phenotype in T and NK cells. In summary, we demonstrated that galunisertib, a clinical stage TGFβ 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. |
| التعليقات: |
Update in: Nat Commun. 2024 Feb 14;15(1):1348. (PMID: 38355731) |
| معلومات مُعتمدة: |
P51 OD011104 United States OD NIH HHS |
| تواريخ الأحداث: |
Date Created: 20231128 Latest Revision: 20240226 |
| رمز التحديث: |
20240226 |
| مُعرف محوري في PubMed: |
PMC10680555 |
| DOI: |
10.1101/2023.09.05.556422 |
| PMID: |
38014094 |
| قاعدة البيانات: |
MEDLINE |
