Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo
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 J. Villinger, and Elena Martinelli
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Published November 22, 2023 - More info
JCI Insight. 2023;8(22):e176882. https://doi.org/10.1172/jci.insight.176882.
© 2023 The American Society for Clinical Investigation
Related article:
Abstract
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 antiretroviral therapy (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 inhibitor, galunisertib. We tested the effect of galunisertib in SIV-infected, ART-treated macaques by monitoring SIV-env expression via PET/CT using the 64Cu-DOTA-F(ab′)2 p7D3 probe, along with plasma and tissue viral loads (VLs). Exogenous TGF-β reduced HIV-1 reactivation in U1 and ACH-2 models. Galunisertib increased HIV-1 latency reversal ex vivo and in PBMCs from HIV-1–infected, ART-treated, aviremic donors. In vivo, oral galunisertib promoted increased total standardized uptake values 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 plasma VLs. 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.
Authors
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 J. Villinger, Elena Martinelli
Original citation JCI Insight. 2022;7(21):e162290. https://doi.org/10.1172/jci.insight.162290
Citation for this corrigendum: JCI Insight. 2023;8(22):e176882. https://doi.org/10.1172/jci.insight.176882
After publication of this article, the authors became aware that the PET/CT scans for animal A14X004 presented in Figure 3F and Supplemental Video 5 were incorrectly scaled by the analytical software due to an input error. Due to PET and CAT misalignment, the nasal associated lymphoid tissue (NALT) data for A14X004 has been removed from Figure 3H. The correct Figure 3, F and H, and the updated figure legend parts are shown below.
In the online version, Supplemental Video 5 has been updated. The original Supplemental Video 8 showed the correct scaling of animal A14X004 and has been removed to avoid redundancy. The corresponding figure legends for the Supplemental Videos have been updated as well as the Supplemental Video callouts. The text of the Results section has been amended to remove statements regarding an increase of PET signal in NALTs, the spinal cord, and the area surrounding the heart in animal A14X004. The Methods section has also been updated to remove reference to the use of the mask function to reduce the signal within the contour to background levels for A14X004. The text has been updated in the HTML version and the PDF. The Journal has also published an online version of the original article with the incorrect statements crossed out and the modified text printed in red (Supplemental File, Redaction). The authors have stated the changes do not affect any of the conclusions.
(C–F) Representative images from the PET/CT scans of 4 out of 5 animals with increased PET signal following galunisertib treatment. (G and H) SUVtot for different anatomical areas (regions of interest) are shown before and after galunisertib treatment (Gut, small and large intestine; LN, axillary LNs; NALT, nasal associated lymphoid tissues; SPL, spleen). A14X004 NALT was excluded because of PET and CT misalignment. Data from baseline (BL) and postgalunisertib weeks 1 and 2 (W1/2) were compared using Wilcoxon matched pairs nonparametric test, and the differences were nonsignificant with α > 0.05.
The authors regret the errors.
