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.
Highlights
The TNF-related apoptosis inducing ligand (TRAIL):TRAIL receptor system has been implicated in the pathogenesis of a variety of malignant and infectious disorders, including HIV infection
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
HIV-infected T Cells Express TRAIL and TRAIL Receptors, but Do Not Undergo Paracrine TRAIL-induced Death—Using primary CD4 T cells from HIV-negative donors, we evaluated whether changes in TRAIL:TRAIL receptor system occurred following acute HIV infection
Summary
The TRAIL:TRAIL receptor system has been implicated in the pathogenesis of a variety of malignant and infectious disorders, including HIV infection. The observation that HIV infection per se (28) or Tat (29) treatment of monocytoid cells up-regulates TRAIL has prompted an alternate model, whereby TRAIL:TRAIL receptor interactions serve as a cause of bystander cell death (30, 31). This latter model is supported by correlative associations between TRAIL production and viral replication (32), as well as peripheral blood lymphocyte-NODSCID mouse studies (33) in which neutralizing anti-TRAIL antibody reduced the rate of CD4 T cell decline following HIV infection. These data suggest that TRAIL-s is a compensatory adaptation of HIV-infected cells that counters the host’s attempts at infected cell eradication by TRAIL-mediated effector mechanisms
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