Journal
CELL REPORTS MEDICINE
Volume 1, Issue 3, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2020.100037
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Funding
- University of California San Diego Center for AIDS Research (CFAR), a National Institute of Health (NIH) [P30 AI036214]
- NIMH
- NIDA
- NICHD
- NHLBI
- NIA
- NIGMS
- NIDDK
- NIH/NIAID [R01 AI124843]
- National Cancer Institute of the NIH [R01 CA195227]
- James B. Pendleton Charitable Trust
- NIAID
- NCI
- Cancer Center Support Grant [P30 CA030199]
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Shock and kill strategies focus on purging the latent HIV-1 reservoir by treating infected individuals with therapeutics that activate the latent virus and subsequently eliminating infected cells. We have previously reported that induction of non-canonical nuclear factor kappa B (NF-kappa B) signaling through a class of small-molecule antagonists known as Smac mimetics can reverse HIV-1 latency. Here, we describe the development of Ciapavir (SBI-0953294), a molecule specifically optimized for HIV-1 latency reversal that was found to be more efficacious as a latency-reversing agent than other Smac mimetics under clinical development for cancer. Critically, this molecule induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.
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