Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.162290 |
| _version_ | 1827768072347320320 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Sadia Samer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:04Z |
| format | Article |
| id | doaj.art-d91bfe3dac314d9ab922f0f232b2155b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:04Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d91bfe3dac314d9ab922f0f232b2155b2023-11-07T16:24:48ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-06-01721Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivoSadia SamerYanique ThomasMariluz AraíngaCrystal CarterLisa M. ShirreffMuhammad S. ArifJuan M. AvitaInes FrankMichael D. McRavenChristopher T. ThuruthiyilVeli B. HeybeliMeegan R. AndersonBenjamin OwenArsen GaisinDeepanwita BoseLacy M. SimonsJudd F. HultquistJames ArthosClaudia CicalaIrini SeretiPhilip J. SantangeloRamon Lorenzo-RedondoThomas J. HopeFrancois J. VillingerElena MartinelliTGF-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.https://doi.org/10.1172/jci.insight.162290AIDS/HIV |
| spellingShingle | 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 Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo JCI Insight AIDS/HIV |
| title | Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo |
| title_full | Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo |
| title_fullStr | Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo |
| title_full_unstemmed | Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo |
| title_short | Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responses in vivo |
| title_sort | blockade of tgf β signaling reactivates hiv 1 siv reservoirs and immune responses in vivo |
| topic | AIDS/HIV |
| url | https://doi.org/10.1172/jci.insight.162290 |
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