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

Lars Pache,Matthew D Marsden,Peter Teriete,Alex J Portillo,Dominik Heimann,Jocelyn T Kim,Mohamed S.A Soliman,Melanie Dimapasoc,Camille Carmona,Maria Celeridad,Adam M Spivak,Vicente Planelles,Nicholas D.P Cosford,Jerome A Zack,Sumit K Chanda

doi:10.1016/j.xcrm.2020.100037

Abstract

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.

Highlights

The development of combination antiretroviral therapy (ART) has enabled the suppression of HIV-1 replication to undetectable levels
We previously reported that Smac mimetic compounds that can target the inhibitor of apoptosis protein cIAP1 (Birc2) harbor latency-reversing agents (LRAs) activity.[28]
Bivalent Smac Mimetics Harbor Greater Potency as LRAs Than Monovalent Compounds We have previously demonstrated that latency reversal of HIV-1 can be promoted in in vitro and ex vivo systems through pharmacological manipulation of the non-canonical nuclear factor kB (NF-kB) pathway using the Smac mimetic compound SBI-0637142.28 This molecule modestly induced HIV-1 latency ex vivo in CD4+ T cells from ART-suppressed aviremic HIV-infected patients as a single agent; robust activity was observed when administered in combination with the histone deacetylase inhibitors (HDACis) panobinostat

Summary

Introduction

The development of combination antiretroviral therapy (ART) has enabled the suppression of HIV-1 replication to undetectable levels. The existence of latent viral reservoirs, persisting for decades, can lead to renewed viremia upon treatment interruption.1 ‘‘Shock and kill’’ approaches aim to deplete the latent reservoir by treating patients with therapeutics that mediate latency reversal and the subsequent elimination of infected cells.[2] The development of safe, potent, and effective latency-reversing agents (LRAs) is an important step that would disencumber HIV-1-infected patients of life-long ART regimens. To achieve this goal, LRAs seek to safely decloak the small but persistent reservoir of latently infected cells. A safe and effective modality for HIV-1 latency reversal continues to represent a critical unmet therapeutic need

Methods

Results

Conclusion