Human immunodeficiency virus (HIV), which causes AIDS, is a persistent infection of T cells and can lead to cell death by apoptosis, which contributes to the compromised immune response. However, as a persistent infection, HIV has also developed strategies to prevent all infected cells from undergoing apoptosis. Schnepple et al. identified one such mechanism of evasion of apoptosis by showing that infected T cells produce a short form of the proapoptotic ligand TRAIL, which is a member of the tumor necrosis superfamily and interacts with five receptors. Two produce proapoptotic signals (TRAIL-R1 and TRAIL-R2), and three act as decoys and antagonize cell death (TRAIL-R3, TRAIL-R4, and ostoprotegrin). Infection of primary T cells from noninfected donors resulted in an increase in the abundance of TRAIL, TRAIL-R1, TRAIL-R2, and TRAIL-R4; however, viability was not increased when the cells were treated with a neutralizing antibody against TRAIL. Supernatants from infected T cells, but not uninfected cells, contained an 11-kD protein recognized by a polyclonal TRAIL antibody, and addition of supernatants from the infected cells to Jurkat T cells (a T cell line) reduced TRAIL-induced cell death. This 11-kD TRAIL protein (TRAIL-s, for TRAIL-short) was the result of alternative splicing of the TRAIL transcript in infected cells. Several independent assays demonstrated that TRAIL-s bound to TRAIL-R2 but not to TRAIL-R1. Stable expression of a tagged form of TRAIL-s in Jurkat cells reduced cell death in response to exogenous TRAIL, and knocking down TRAIL-s in one of these TRAIL-s–expressing cell lines enhanced TRAIL-induced cell death. To confirm the in vivo relevance of TRAIL-s, the authors showed that the abundance of TRAIL-s was higher in sera from HIV-infected patients and the amount correlated with viral load. Thus, production of an antagonistic form of TRAIL appears to contribute to survival of HIV-infected T cells and may contribute to viral persistence.
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, A. D. Badley, Isolation of a TRAIL antagonist from the serum of HIV-infected patients. J. Biol. Chem. 286, 35742–35754 (2011). [Abstract] [Full Text]