| Autor: |
S Samer, Y Thomas, M Araínga, CM Carter, LM Shirreff, MS Arif, JM Avita, I Frank, M McRaven, CT Thuruthiyil, V Heybeli, MR Anderson, B Owen, A Gaisin, D Bose, LM Simons, JF Hultquist, J Arthos, C Cicala, I Sereti, P Santangelo, R Lorenzo-Redondo, TJ Hope, FJ Villinger, E Martinelli |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.05.13.489595 |
| Popis: |
Elevated levels of TGF-β, a potent immunosuppressive factor, are present in HIV-1 infected individuals even after years of antiretroviral therapy (ART). TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent one of the main cellular reservoirs after long term ART and the low inducibility of the latent provirus constitutes one of the major obstacles to “kick and kill” cure strategies. We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal. To test our hypothesis, we comparedex vivomodels of HIV-1 latency reactivation with and without TGF-β and a TGF-β type 1 receptor (TGFBR1) inhibitor, galunisertib. We also tested the effect of galunisertib in SIV infected, ART treated macaques by monitoring SIV envelope (env) protein expression via PET/CT using the Cu64-anti gp120 Fab (7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-1β reduced HIV-1 reactivation in U1 and ACH2 latency models. Galunisertib increased HIV-1 latency reversal both inex vivomodels and in PBMC from HIV-1 infected, cART treated aviremic donors.In vivo, oral galunisertib promoted increased SIV env protein total standardized uptake values (SUVtot) in PET/CT images of tissues (gut and lymph nodes) of 5 out of 7 aviremic, long-term ART-treated, SIV-infected, macaques. This increase correlated with an increase in SIV RNA in gut tissue. Two out of 7 animals also exhibited increases in plasma viral load. Higher anti-SIV T cell responses and anti-SIV env antibody titers were detected after galunisertib treatment in most animals. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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