Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice
Summary: Latent viral reservoirs (VRs) represent a main barrier to HIV cure. Thus, developing new approaches that can purge and eliminate VRs paves the path toward achieving an HIV-1 cure. APG-1387, a bivalent SMAC mimetic (SM), efficiently reactivates latent HIV expression in T cell line models and...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422402697X |
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| author | Jaspreet Jain Tram N.Q. Pham Sharmin Begum Maria Carmen Romero-Medina Nicolas Bellini Yuanyi Li Frédéric Dallaire Kathie Béland Natasha Patey Jean V. Guimond Élie Haddad Yifan Zhai Éric A. Cohen |
| author_facet | Jaspreet Jain Tram N.Q. Pham Sharmin Begum Maria Carmen Romero-Medina Nicolas Bellini Yuanyi Li Frédéric Dallaire Kathie Béland Natasha Patey Jean V. Guimond Élie Haddad Yifan Zhai Éric A. Cohen |
| author_sort | Jaspreet Jain |
| collection | DOAJ |
| description | Summary: Latent viral reservoirs (VRs) represent a main barrier to HIV cure. Thus, developing new approaches that can purge and eliminate VRs paves the path toward achieving an HIV-1 cure. APG-1387, a bivalent SMAC mimetic (SM), efficiently reactivates latent HIV expression in T cell line models and enhances active caspase 3 expression, a condition that typically leads to apoptosis. In primary CD4+ T cells infected with a dual reporter-encoded HIV, APG-1387 decreases latently infected cells without a notable effect on productively infected cells. In virally suppressed humanized (hu)-BLT mice, APG-1387 augments cell-associated viral RNA and potently reduces HIV DNA-containing cells without modulating T cell activation or proliferation. Upon antiretroviral therapy (ART) interruption, HIV rebound was decreased in APG-1387-treated humanized mice (hu-mice), and the viremia maintained at levels below that of pre-ART. Thus, the ability of APG-1387 to affect VRs and decrease viral rebound highlights the potential of bivalent SMs in HIV cure strategies. |
| format | Article |
| id | doaj-art-b2419a44a52a4d4982d6d7e0a8ba0880 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-b2419a44a52a4d4982d6d7e0a8ba08802024-12-22T05:29:28ZengElsevieriScience2589-00422024-12-012712111470Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized miceJaspreet Jain0Tram N.Q. Pham1Sharmin Begum2Maria Carmen Romero-Medina3Nicolas Bellini4Yuanyi Li5Frédéric Dallaire6Kathie Béland7Natasha Patey8Jean V. Guimond9Élie Haddad10Yifan Zhai11Éric A. Cohen12Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montréal, QC H4A 3J1, CanadaInstitut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, CanadaInstitut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montréal, QC H4A 3J1, CanadaInstitut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, CanadaInstitut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, CanadaCHU Sainte-Justine Azrieli Research Center, Montréal, QC H3T 1C5, CanadaInstitut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, CanadaCHU Sainte-Justine Azrieli Research Center, Montréal, QC H3T 1C5, CanadaCHU Sainte-Justine Azrieli Research Center, Montréal, QC H3T 1C5, Canada; Department of Pathology and Cellular Biology, Université de Montréal, Montréal, QC H3T 1J4, CanadaCentre de Santé et de Services Sociaux Jeanne-Mance, Montréal, QC H2X 1K6, CanadaDepartment of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada; CHU Sainte-Justine Azrieli Research Center, Montréal, QC H3T 1C5, Canada; Department of Pediatrics, Université de Montréal, Montréal, QC H3T 1J4, CanadaAscentage Pharma (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, China; Ascentage Pharma Group, Rockville, MD 20850, USAInstitut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada; Corresponding authorSummary: Latent viral reservoirs (VRs) represent a main barrier to HIV cure. Thus, developing new approaches that can purge and eliminate VRs paves the path toward achieving an HIV-1 cure. APG-1387, a bivalent SMAC mimetic (SM), efficiently reactivates latent HIV expression in T cell line models and enhances active caspase 3 expression, a condition that typically leads to apoptosis. In primary CD4+ T cells infected with a dual reporter-encoded HIV, APG-1387 decreases latently infected cells without a notable effect on productively infected cells. In virally suppressed humanized (hu)-BLT mice, APG-1387 augments cell-associated viral RNA and potently reduces HIV DNA-containing cells without modulating T cell activation or proliferation. Upon antiretroviral therapy (ART) interruption, HIV rebound was decreased in APG-1387-treated humanized mice (hu-mice), and the viremia maintained at levels below that of pre-ART. Thus, the ability of APG-1387 to affect VRs and decrease viral rebound highlights the potential of bivalent SMs in HIV cure strategies.http://www.sciencedirect.com/science/article/pii/S258900422402697XImmunologyVirologyNatural sciencesBiological sciences |
| spellingShingle | Jaspreet Jain Tram N.Q. Pham Sharmin Begum Maria Carmen Romero-Medina Nicolas Bellini Yuanyi Li Frédéric Dallaire Kathie Béland Natasha Patey Jean V. Guimond Élie Haddad Yifan Zhai Éric A. Cohen Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice iScience Immunology Virology Natural sciences Biological sciences |
| title | Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice |
| title_full | Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice |
| title_fullStr | Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice |
| title_full_unstemmed | Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice |
| title_short | Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice |
| title_sort | bivalent smac mimetic apg 1387 reduces hiv reservoirs and limits viral rebound in humanized mice |
| topic | Immunology Virology Natural sciences Biological sciences |
| url | http://www.sciencedirect.com/science/article/pii/S258900422402697X |
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