Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs <i>In Vivo</i>.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33205060.
- Also identified by DOI 10.1016/j.xcrm.2020.100037 and PMC identifier 7659604.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
"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 κB (NF-κB) 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 <i>in vivo</i> in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation. This study provides proof of concept for the <i>in vivo</i> 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.
Medical subject headings
- Anti-Retroviral Agents
- HIV Infections
- HIV-1
- NF-kappa B
- Signal Transduction
- Virus Latency