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 the main cellular reservoir after long-term ART. We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal. To test our hypothesis, we compared HIV-1 latency models with and without TGF-β and a TGF-β-Type-1 receptor (TGFBR1) inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the Cu64-anti-gp120 Fab(7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-β reduced HIV-1 reactivation in U1 and ACH2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMC from HIV-1 infected, ART-treated aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values (SUVtot) in PET/CT images in 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 the gut. Two of the 7 animals also exhibited increases in pVL. Higher anti-SIV T cell responses and antibody titers were detected after galunisertib treatment. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.
Sadia Samer, Yanique Thomas, Mariluz Araínga, Crystal Carter, Lisa M. Shirreff, Muhammad S. Arif, Juan M. Avita, Ines Frank, Michael D. McRaven, Christopher T. Thuruthiyil, Veli B. Heybeli, Meegan R. Anderson, Benjamin Owen, Arsen Gaisin, Deepanwita Bose, Lacy M. Simons, Judd F. Hultquist, James Arthos, Claudia Cicala, Irini Sereti, Philip J. Santangelo, Ramon Lorenzo-Redondo, Thomas J. Hope, Francois Villinger, Elena Martinelli