Bivalent SMAC mimetic APG-1387 reduces HIV reservoirs and limits viral rebound in humanized mice
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<sup>+</sup> 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.
Authors
- Jaspreet Jain
- Maria Carmen Romero-Medina
- Yifan Zhai (ORCID: https://orcid.org/0000-0003-1672-2262)
- Éric A. Cohen (ORCID: https://orcid.org/0000-0003-1269-3791)
- Natasha Patey
- Kathie Béland (ORCID: https://orcid.org/0000-0001-5503-365X)
- Tram N. Q. Pham (ORCID: https://orcid.org/0000-0001-8238-9061)
- Élie Haddad (ORCID: https://orcid.org/0000-0003-2446-6879)
- Jean Guimond (ORCID: https://orcid.org/0000-0002-1790-2591)
- Nicolas Bellini
- Frédéric Dallaire (ORCID: https://orcid.org/0000-0002-0489-2523)
- Yuanyi Li (ORCID: https://orcid.org/0000-0002-7195-1247)
- Sharmin Begum (ORCID: https://orcid.org/0000-0002-5161-5916)
Institutions
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Ascepion Pharmaceuticals (China) (CN)
- Centre de Santé et de Services Sociaux Cavendish (CA)
- Montreal Clinical Research Institute (CA)
- Bridge Pharma (United States) (US)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- iScience
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1016/j.isci.2024.111470
- Citations
- 4
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Styrelsen för Internationellt Utvecklingssamarbete
- Case Western Reserve University
- School of Medicine, Case Western Reserve University
- McGill University
- Ascentage Pharma
- National Institutes of Health
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- National Institute of Allergy and Infectious Diseases