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

  • Cell Rep Med. 2020 Jun 23;1(3):100037. doi: 10.1016/j.xcrm.2020.100037.
Lars Pache  1 ,  Matthew D Marsden  2 ,  Peter Teriete  3 ,  Alex J Portillo  1 ,  Dominik Heimann  3 ,  Jocelyn T Kim  4 ,  Mohamed S A Soliman  5 ,  Melanie Dimapasoc  5 ,  Camille Carmona  5 ,  Maria Celeridad  3 ,  Adam M Spivak  6 ,  Vicente Planelles  6 ,  Nicholas D P Cosford  3 ,  Jerome A Zack  2  5 ,  Sumit K Chanda  1
Affiliations
  • 1. Infectious and Inflammatory Disease Center, Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 2. Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3. Cell Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 4. Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 5. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6. Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
PMID: 33205060 DOI: 10.1016/j.xcrm.2020.100037
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 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.

Keywords
BLT mouse model; HIV; HIV cure; LRA; Smac mimetics; humanized mouse model; latency; latency reversal agents; non-canonical NF-κB; shock and kill.
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