TRAIL

Figure 6-G-3.  Schematic drawing of TRAIL receptors, which can be divided into two categories:
Death receptors:  TRAIL-R1 and TRAIL-R2 contain the death domain, capable of inducing apoptosis.
Decoy receptors:  TRAIL-R3 and TRAIL-R5  lack the death domain while TRAIL-R4 contains a truncated non-functional death domain.  These three receptors can bind to TRAIL, but cannot induce apoptosis.  TRAIL-R5 is secreted to the extracellular fluid.  All other receptors are transmembrane proteins.

TRAIL (TNF-related apoptosis-inducing ligand) is a protein consisting of 281 amino acids.  It is also called APO-2L.  Five TRAIL receptors have been identified (above figure).  Two of them can lead to apoptosis.  The other three serve as "decoy" receptors.  A cell expressing more decoy receptors is more likely to survive upon binding of the death ligands.

TRAIL as Cancer Therapeutic

TRAIL has been demonstrated to kill a wide variety of tumor cells with minimal effects on normal cells.  This is because TRAIL's death receptors (TRAIL-R1 and TRAIL-R2) are mainly expressed in transformed cells while its decoy receptors (TRAIL-R3, TRAIL-R4 and TRAIL-R5) are expressed in normal cells.  The major concern about using TRAIL as a therapeutic is its toxicity to human hepatocytes.  TRAIL can cause significant death of normal human hepatocytes, but has no effect on the normal hepatocytes of mice.  In the future, as we have better understanding on the regulation of receptor expression and signaling cascades, it may be possible to save normal cells from the toxic effects of TRAIL. 

TRAIL and AIDS

AIDS (acquired immune deficiency syndrome) is characterized by the depletion of T cells.  It has been demonstrated that HIV can induce apoptosis in both infected cells and their neighboring (bystander) cells (review).  Recently, it was further shown that those bystander cells were killed mainly through the TRAIL-mediated apoptosis.  Experimental results suggest that the extracellular Tat protein, released from HIV-infected cells, can induce production of TRAIL by macrophages, resulting in the apoptosis of bystander T cells  (reference).

As mentioned above, TRAIL has minimal effects on normal cells (except for human hepatocytes).  Then, how could T cells in HIV patients become susceptible to TRAIL?  Presumably, the regulation of TRAIL receptor expression in bystander cells should be altered, but the detailed mechanism is not known.  A recent report indicates that the HIV's surface protein, gp120, is involved.

The most challenging question in AIDS therapy is how to eradicate the HIV that persists in "latent reservoirs" (e.g., resting memory T cells) even after prolonged  antiretroviral therapy (reference).  Recently, it was shown that TRAIL can kill the latent cells (reference ).  Since TRAIL also kills the transformed bystander cells, it is recommended that TRAIL be given to patients after prolonged HAART (highly active antiretroviral therapy).  At this time, only the latent cells remain and their neighboring cells may not be susceptible to TRAIL.

Review Articles:

Tissue Distribution of the Death Ligand TRAIL and Its Receptors - J. Histochemistry and Cytochemistry, 2004.