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J. Biol. Chem. 286 (41): 35742-35754

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: The TRAIL:TRAIL receptor system has been implicated in the pathogenesis of a variety of malignant and infectious disorders, including HIV infection.

Results: We show that HIV causes production of a novel TRAIL splice variant, that we call TRAIL-short, which binds TRAIL R2, antagonizes TRAIL signaling, and is present in HIV patient samples.

Conclusion: Introduction of TRAIL-short causes resistance to TRAIL, whereas knockdown restores sensitivity.

Significance: The identification of TRAIL-short impacts our understanding of TRAIL sensitivity and has implications for the pathogenesis of both infectious and malignant pathogenesis.

Isolation of a TRAIL Antagonist from the Serum of HIV-infected Patients*Formula

David J. Schnepple{ddagger}§, Brett Shepard{ddagger}, Gary D. Bren{ddagger}, Nathan W. Cummins{ddagger}, Sekar Natesampillai{ddagger}, Sergey Trushin{ddagger}, Alicia Algeciras-Schimnich{ddagger}, Xue W. Meng||, Amy M. Sainski{ddagger}**, Stacey A. Rizza{ddagger}, Scott H. Kaufmann||**, , and Andrew D. Badley{ddagger}1

From the {ddagger}Division of Infectious Diseases,
the §Program in Molecular Neuroscience,
the ||Division of Oncology Research,
the **Department of Molecular Pharmacology, and
the Program in Translational Immunovirology and Biodefense, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

ABSTRACT Back to Top

Abstract: Virus-host interactions are characterized by the selection of adaptive mechanisms by which to evade pathogenic and defense mechanisms, respectively. In primary T cells infected with HIV, HIV infection up-regulates TNF-related apoptosis inducing ligand (TRAIL) and death-inducing TRAIL receptors, but blockade of TRAIL:TRAIL receptor interaction does not alter HIV-induced cell death. Instead, HIV infection results in a novel splice variant that we call TRAIL-short (TRAIL-s), which antagonizes TRAIL-R2. In HIV patients, plasma TRAIL-s concentration increases with increasing viral load and renders cells resistant to TRAIL-induced death. Knockdown of TRAIL-s abrogates this resistance. We propose that TRAIL-s is a novel adaptive mechanism of apoptosis resistance acquired by HIV-infected cells to avoid their elimination by TRAIL-dependent effector mechanism.

Key Words: Apoptosis • HIV • T Cell • Trail • Viral Replication • TRAIL Inhibitor

Received for publication June 21, 2011. Revision received August 17, 2011.

1 To whom correspondence should be addressed: Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-3747; Fax: 507-284-3757; E-mail: badley.andrew{at}

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