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

J. Biol. Chem., 14 October 2011
Vol. 286, Issue 41, p. 35742-35754
DOI: 10.1074/jbc.M111.274639

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

  1. David J. Schnepple§,
  2. Brett Shepard,
  3. Gary D. Bren,
  4. Nathan W. Cummins,
  5. Sekar Natesampillai,
  6. Sergey Trushin,
  7. Alicia Algeciras-Schimnich,
  8. Xue W. Meng,
  9. Amy M. Sainski**,
  10. Stacey A. Rizza,
  11. Scott H. Kaufmann** and
  12. Andrew D. Badley,1
  1. From the Division of Infectious Diseases,
  2. the §Program in Molecular Neuroscience,
  3. the Division of Oncology Research,
  4. the **Department of Molecular Pharmacology, and
  5. the Program in Translational Immunovirology and Biodefense, Mayo Clinic College of Medicine, Rochester, Minnesota 55905
  1. 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}

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.


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.

  • Apoptosis
  • HIV
  • T Cell
  • Trail
  • Viral Replication
  • TRAIL Inhibitor


  • * This work was supported, in whole or in part, by National Institutes of Health Grant R01 AI62261 (to A. D. B.).

  • Embedded Image The on-line version of this article (available at contains supplemental Fig. S1.

  • Received June 21, 2011.
  • Revision received August 17, 2011.


D. J. Schnepple, B. Shepard, G. D. Bren, N. W. Cummins, S. Natesampillai, S. Trushin, A. Algeciras-Schimnich, X. W. Meng, A. M. Sainski, S. A. Rizza, S. H. Kaufmann, and A. D. Badley, Isolation of a TRAIL Antagonist from the Serum of HIV-infected Patients. J. Biol. Chem. 286, 35742-35754 (2011).
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