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

Cell Reports Medicine (Jun 2020)

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

Affiliations

Lars Pache: Infectious and Inflammatory Disease Center, Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Matthew D. Marsden: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Peter Teriete: Cell Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Alex J. Portillo: Infectious and Inflammatory Disease Center, Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Dominik Heimann: Cell Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Jocelyn T. Kim: Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Mohamed S.A. Soliman: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Melanie Dimapasoc: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Camille Carmona: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Maria Celeridad: Cell Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Adam M. Spivak: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Vicente Planelles: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Nicholas D.P. Cosford: Cell Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Jerome A. Zack: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Sumit K. Chanda: Infectious and Inflammatory Disease Center, Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Corresponding author

Journal volume & issue: Vol. 1, no. 3
p. 100037

Abstract

Read online

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.

Published in Cell Reports Medicine

ISSN: 2666-3791 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Medicine (General)
Website: https://www.cell.com/cell-reports-medicine

About the journal

Abstract

Keywords