Comment on Herbeuval et al, page 2458
Several recent reports have documented the critical contribution of TRAIL to T-cell depletion during HIV infection. In this issue of Blood, Herbeuval and colleagues provide evidence that antigen-presenting cells are a major source of this death ligand when stimulated by HIV particles.
The dramatic loss of CD4+ lymphocytes, which accompanies infection by human immunodeficiency virus (HIV), is a critical event leading to AIDS. Increased apoptosis is regarded as a primary cause of CD4+ T-cell depletion in HIV-infected individuals, but the mechanism by which this occurs is still a matter of debate.1 Although HIV replication can kill infected cells, direct cytopathic effects cannot account for the massive loss of CD4+ T cells observed in patients, as only a small fraction of them are actually infected. Although chronic activation, CD4 triggering by HIV gp120, action of other viral proteins, and production of cytotoxic ligands by different cells have been involved in HIV-induced depletion of uninfected CD4+ T cells, a comprehensive model is still missing.
Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) recently captured attention when it was discovered that uninfected T cells from HIV-infected individuals are abnormally sensitive to this death factor.2 In addition, TRAIL was shown to mediate apoptosis of uninfected CD4+ T cells in a model of HIV-1–infected human peripheral blood lymphocyte–transplanted nonobese diabetic severe combined immunodeficient (hu-PBL-NOD-SCID) mice.3 Although several reports have documented the induction of this death factor in HIV-infected patients, TRAIL-producing cells and mechanisms of induction have not yet been elucidated.
In this issue, Herbeuval and colleagues compared soluble TRAIL (sTRAIL) expression levels in plasma samples from treated versus untreated HIV-infected patients. Their data show a strong correlation between sTRAIL concentration and viral load, suggesting that HIV particles could directly trigger TRAIL expression. This hypothesis was tested using HIV particles inactivated with aldrithiol-2 (AT-2).4 By modifying free thiol groups on virion internal proteins, AT-2 treatment results in inactivation of retroviral infectivity without compromising the integrity of the virion envelope. Such particles were used to stimulate peripheral blood mononuclear cells (PBMCs) from healthy donors, and were shown to induce sTRAIL expression. Stimulation of purified cells led to the conclusion that monocytes are the major source of sTRAIL. Most importantly, the data from Herbeuval and colleagues demonstrate that TRAIL expression can be triggered in the absence of viral replication. Although Tat protein from HIV was previously shown to induce TRAIL,5 Herbeuval and colleagues have characterized an alternative mechanism that appears very efficient. They provide strong evidence that early engagement of CD4 by envelope gp120 activates a type I interferon response that results in TRAIL induction.
These data are consistent with a model in which stimulation of antigen-presenting cells by HIV gp120 and Tat triggers TRAIL expression. Interestingly, this model implies that replication-defective virions, which represent more than 99.99% of all HIV particles in patients, can efficiently induce TRAIL synthesis. But why CD4+ T lymphocytes become TRAIL-sensitive in the context of HIV infection is still puzzling. As recently proposed, such a sensitization process could involve the serial engagement of CD4 and the T-cell receptor by gp120 and major histocompatibility complex class II molecules expressed at the su rface of HIV virions.4 ▪
