Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling
Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. Howe...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00267/full |
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| author | Florent Colomb Leila B. Giron Thomas A. Premeaux Brooks I. Mitchell Toshiro Niki Toshiro Niki Emmanouil Papasavvas Luis J. Montaner Lishomwa C. Ndhlovu Mohamed Abdel-Mohsen |
| author_facet | Florent Colomb Leila B. Giron Thomas A. Premeaux Brooks I. Mitchell Toshiro Niki Toshiro Niki Emmanouil Papasavvas Luis J. Montaner Lishomwa C. Ndhlovu Mohamed Abdel-Mohsen |
| author_sort | Florent Colomb |
| collection | DOAJ |
| description | Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. However, the signaling mechanisms underlying Gal-9-mediated viral transcription remain unclear. Given that galectins are known to modulate T cell receptor (TCR)-signaling, we hypothesized that Gal-9 modulates HIV transcriptional activity, at least in part, through inducing TCR signaling pathways. Gal-9 induced T cell receptor ζ chain (CD3ζ) phosphorylation (11.2 to 32.1%; P = 0.008) in the J-Lat HIV latency model. Lck inhibition reduced Gal-9-mediated viral reactivation in the J-Lat HIV latency model (16.8–0.9%; P < 0.0001) and reduced both Gal-9-mediated CD4+ T cell activation (10.3 to 1.65% CD69 and CD25 co-expression; P = 0.0006), and IL-2/TNFα secretion (P < 0.004) in primary CD4+ T cells from HIV-infected individuals on suppressive ART. Using phospho-kinase antibody arrays, we found that Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules ERK1/2 (26.7-fold) and CREB (6.6-fold). ERK and CREB inhibitors significantly reduced Gal-9-mediated viral reactivation (16.8 to 2.6 or 12.6%, respectively; P < 0.0007). Given that the immunosuppressive rapamycin uncouples HIV latency reversal from cytokine-associated toxicity, we also investigated whether rapamycin could uncouple Gal-9-mediated latency reactivation from its concurrent pro-inflammatory cytokine production. Rapamycin reduced Gal-9-mediated secretion of IL-2 (4.4-fold, P = 0.001) and TNF (4-fold, P = 0.02) without impacting viral reactivation (16.8% compared to 16.1%; P = 0.2). In conclusion, Gal-9 modulates HIV transcription by activating the TCR-downstream ERK and CREB signaling pathways in an Lck-dependent manner. Our findings could have implications for understanding the role of endogenous galectin interactions in modulating TCR signaling and maintaining chronic immune activation during ART-suppressed HIV infection. In addition, uncoupling Gal-9-mediated viral reactivation from undesirable pro-inflammatory effects, using rapamycin, may increase the potential utility of recombinant Gal-9 within the reversal of HIV latency eradication framework. |
| first_indexed | 2024-12-12T19:56:08Z |
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| id | doaj.art-3d2e327c70ed42f084495df2abed41f0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T19:56:08Z |
| publishDate | 2019-02-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-3d2e327c70ed42f084495df2abed41f02022-12-22T00:13:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-02-011010.3389/fimmu.2019.00267436546Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK SignalingFlorent Colomb0Leila B. Giron1Thomas A. Premeaux2Brooks I. Mitchell3Toshiro Niki4Toshiro Niki5Emmanouil Papasavvas6Luis J. Montaner7Lishomwa C. Ndhlovu8Mohamed Abdel-Mohsen9Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United StatesVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United StatesDepartment of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United StatesDepartment of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United StatesGalPharma Co. Ltd., Takamatsu-shi, Takamatsu, JapanDepartment of Immunology and Immunopathology, Kagawa University, Takamatsu, JapanVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United StatesVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United StatesDepartment of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United StatesVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United StatesEndogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. However, the signaling mechanisms underlying Gal-9-mediated viral transcription remain unclear. Given that galectins are known to modulate T cell receptor (TCR)-signaling, we hypothesized that Gal-9 modulates HIV transcriptional activity, at least in part, through inducing TCR signaling pathways. Gal-9 induced T cell receptor ζ chain (CD3ζ) phosphorylation (11.2 to 32.1%; P = 0.008) in the J-Lat HIV latency model. Lck inhibition reduced Gal-9-mediated viral reactivation in the J-Lat HIV latency model (16.8–0.9%; P < 0.0001) and reduced both Gal-9-mediated CD4+ T cell activation (10.3 to 1.65% CD69 and CD25 co-expression; P = 0.0006), and IL-2/TNFα secretion (P < 0.004) in primary CD4+ T cells from HIV-infected individuals on suppressive ART. Using phospho-kinase antibody arrays, we found that Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules ERK1/2 (26.7-fold) and CREB (6.6-fold). ERK and CREB inhibitors significantly reduced Gal-9-mediated viral reactivation (16.8 to 2.6 or 12.6%, respectively; P < 0.0007). Given that the immunosuppressive rapamycin uncouples HIV latency reversal from cytokine-associated toxicity, we also investigated whether rapamycin could uncouple Gal-9-mediated latency reactivation from its concurrent pro-inflammatory cytokine production. Rapamycin reduced Gal-9-mediated secretion of IL-2 (4.4-fold, P = 0.001) and TNF (4-fold, P = 0.02) without impacting viral reactivation (16.8% compared to 16.1%; P = 0.2). In conclusion, Gal-9 modulates HIV transcription by activating the TCR-downstream ERK and CREB signaling pathways in an Lck-dependent manner. Our findings could have implications for understanding the role of endogenous galectin interactions in modulating TCR signaling and maintaining chronic immune activation during ART-suppressed HIV infection. In addition, uncoupling Gal-9-mediated viral reactivation from undesirable pro-inflammatory effects, using rapamycin, may increase the potential utility of recombinant Gal-9 within the reversal of HIV latency eradication framework.https://www.frontiersin.org/article/10.3389/fimmu.2019.00267/fullHIVlectinsgalectin-9T cell receptorTCR signalingrapamycin |
| spellingShingle | Florent Colomb Leila B. Giron Thomas A. Premeaux Brooks I. Mitchell Toshiro Niki Toshiro Niki Emmanouil Papasavvas Luis J. Montaner Lishomwa C. Ndhlovu Mohamed Abdel-Mohsen Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling Frontiers in Immunology HIV lectins galectin-9 T cell receptor TCR signaling rapamycin |
| title | Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling |
| title_full | Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling |
| title_fullStr | Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling |
| title_full_unstemmed | Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling |
| title_short | Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK Signaling |
| title_sort | galectin 9 mediates hiv transcription by inducing tcr dependent erk signaling |
| topic | HIV lectins galectin-9 T cell receptor TCR signaling rapamycin |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00267/full |
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