| Autor: |
Nichols Doyle R; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA., Yang V; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA., Kayode YI; Department of Microbiology and Immunology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY 13210, USA., Damoiseaux R; California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.; Department of Bioengineering, University of California, Los Angeles, CA 90095, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA., Taylor HE; Department of Microbiology and Immunology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY 13210, USA., Fregoso OI; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA. |
| Abstrakt: |
The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the "kick and kill" (also called "shock and kill") approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair-highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency. |
