SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages

Grant R Campbell,Stephen A Spector,Gang Zhang,Rachel K To

doi:10.1038/s41419-020-02761-x

Abstract

Human immunodeficiency type 1 (HIV)-infected macrophages (HIV-Mφ) are a reservoir for latent HIV infection and a barrier to HIV eradication. In contrast to CD4+ T cells, HIV-Mφ are resistant to the cytopathic effects of acute HIV infection and have increased expression of cell survival factors, including X-linked inhibitor of apoptosis (XIAP), baculoviral IAP repeat containing (BIRC) 2/cIAP1, beclin-1, BCL2, BCL-xl, triggering receptor expressed on myeloid cells 1, mitofusin (MFN) 1, and MFN2. DIABLO/SMAC mimetics are therapeutic agents that affect cancer cell survival and induce cell death. We found that DIABLO/SMAC mimetics (LCL-161, AT-406 (also known as SM-406 or Debio 1143), and birinapant) selectively kill HIV-Mφ without increasing bystander cell death. DIABLO/SMAC mimetic treatment of HIV-Mφ-induced XIAP and BIRC2 degradation, leading to the induction of autophagy and the formation of a death-inducing signaling complex on phagophore membranes that includes both pro-apoptotic or necroptotic (FADD, receptor-interacting protein kinase (RIPK) 1, RIPK3, caspase 8, and MLKL) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacologic inhibition of early stages of autophagy, but not late stages of autophagy, ablated this interaction and inhibited apoptosis. Furthermore, DIABLO/SMAC mimetic-mediated apoptosis of HIV-Mφ is dependent upon tumor necrosis factor signaling. Our findings thus demonstrate that DIABLO/SMAC mimetics selectively induce autophagy-dependent apoptosis in HIV-Mφ.

Highlights

Introduction latently infectedCD4+ T cells are the predominant human immunodeficiency virus type 1 (HIV) reservoir in infected persons on suppressive antiretroviral therapy (ART), other cell types including macrophages serve as important sites of viral persistence[1,2,3]
DIABLO mimetics selectively kill HIV-infected macrophages We previously showed that HIV latently infected CD4+
As SMAC peptidomimetics (SM) induce the rapid degradation of BIRC2 and X-linked inhibitor of apoptosis (XIAP) in cancer cells and HIV-TCM19,24,25,29–31, we evaluated the ability of the SM LCL-161, AT-406, and birinapant to induce BIRC2 and XIAP degradation in uninfected macrophages and HIV-Mφ

Summary

Introduction

CD4+ T cells are the predominant human immunodeficiency virus type 1 (HIV) reservoir in infected persons on suppressive antiretroviral therapy (ART), other cell types including macrophages serve as important sites of viral persistence[1,2,3]. The overexpression of IAPs can inhibit cell death through a number of mechanisms, including direct inhibition of caspases and ubiquitination of receptor-interacting protein kinase (RIPK) 1, an important convergence point between pro-death, pro-survival, and proinflammatory signals. They may play a role in the establishment of HIV latency and cytopathogenesis[22].

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Conclusion