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

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. 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.