Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo

Summary “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 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.

Graphical Abstract

Highlights Ciapavir is a potent Smac mimetic specifically optimized for HIV-1 latency reversal Smac mimetics synergize with bromodomain inhibitors to reverse HIV-1 latency Ciapavir is well tolerated and does not induce broad immune activation Systemic administration of Ciapavir mediates latency reversal in a mouse model

Pache et al. report the development of Ciapavir, a potent small-molecule Smac mimetic optimized for HIV-1 latency reversal. Ciapavir shows favorable pharmacokinetic and pharmacodynamic properties in mice and induces activation of the latent HIV-1 reservoir in vivo in a humanized mouse model in the absence of systemic immune activation.