The TRAIL: TRAILshort Axis in HIV Immunopathology

Abstract

Accelerated loss of HIV-infected and uninfected CD4 T cells is a hallmark of HIV infection that leads to severe immunodeficiency, rendering the host susceptible to opportunistic infections and malignancies. Obstacles to eradicating HIV involve the virus's ability to remain in a quiescent state as latent viral reservoirs and manipulate host defenses to benefit viral survival and persistence of the infected reservoir. Several mechanisms cause CD4 T-cell depletion and recent studies demonstrate the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in this process. Expression of TRAIL and its receptors is upregulated in response to HIV infection. TRAIL interacts with its receptors to activate apoptotic pathways. We recently demonstrated the presence of TRAILshort, a novel splice variant of full-length TRAIL, in the serum of HIV-infected patients. A unique carboxy-terminus allows TRAILshort to bind to death receptors without inducing apoptosis and prevents TRAIL from binding to its receptors, thereby conferring resistance to TRAIL-mediated death. In this review, we describe how the TRAIL: TRAILshort receptor axis modulates apoptosis of different types of immune cells in the context of HIV infection. We also discuss how TRAIL and TRAILshort contribute to the activation of immune cells involved in host defense against HIV and mechanisms that HIV has evolved to manipulate TRAIL for its survival.

FIG. 1:

The IFN-α immune response in HIV infection: When a cell is infected with HIV, the pattern recognition receptors (PPRs) such as TLR7 and TLR9 are activated and signal through the myeloid differentiation primary response 88 (MYD88), and in parallel IFI-16 and cyclic GMP-AMP (cGAMP) synthase (cGAS) are activated and signal through stimulator of IFN genes (STING) to phosphorylate and induce homo-oligomerization of IRF-7 and IRF-3, which translocate to the nucleus and bind to the IFN regulatory binding site (IRFBS) and stimulate the production of IFN. IFN is secreted and binds to the IFN receptors IFNR-1 and IFNR-2, activating of the downstream JAK/STAT signaling. The antiviral defense activity of IFN is mediated through the many ISGs, including tetherin, SAMHD-1, APOBEC-3, and TRAIL. The virus has developed many mechanisms to block these protective ISGs. Vpu blocks tetherin, Vpx blocks SAMHD1, and Vif blocks APOBEC-3. The production of TRAILshort blocks the function of TRAIL, thereby preventing the apoptosis of the infected cells.

FIG. 2:

TRAILshort negatively affects the immune response to HIV infection: TRAILshort is a splice variant of full-length TRAIL that lacks exons 3 and 4. The splicing event introduces a frame shift in exon 5, resulting in a novel 11-amino acid carboxy-terminus. The production of TRAIL short will reduce the apoptosis in the infected CD4 cells and decrease the cytotoxic capacity of NK cells and CD8 T cells, creating a favorable environment for HIV replication.