Credit: GETTY

Viruses are in a constant arms race with the host immune system, hijacking host proteins or modulating their function to ensure survival. Two studies provide novel insights into the battle between human cytomegalovirus (HCMV) and the host, uncovering a role for the viral protein UL141 in dampening innate antiviral defences.

As part of its immune modulation strategy, HCMV interferes with signalling mediated through tumour necrosis factor (TNF) ligands in the target cell. These cytokines protect against viral infections and also have key roles in promoting immune cell apoptosis to limit tissue damage. One such cytokine is TNF-related apoptosis-inducing ligand (TRAIL), which binds to the death receptors (DRs) TRAILR1 and TRAILR2 and triggers apoptosis of the target cell.

UL141 promotes HCMV survival by blocking TRAIL DR surface expression

Interestingly, Smith et al. observed that when fibroblasts were infected with HCMV strains that had been subjected to limited in vitro culture, these cells downregulated the cell surface expression of TRAILR1 and TRAILR2, an effect that was absent in fibroblasts infected with a highly passaged viral strain. The highly passaged virus has lost the UL/b′ genomic region containing the UL141-encoding gene, and further analysis revealed that strains lacking UL141 specifically were unable to downregulate the surface expression of the two TRAIL DRs. Importantly, UL141 was shown to directly interact with TRAILR1 and TRAILR2 and to be sufficient for reducing their expression at the cell surface.

Smith et al. and Nemčovičová et al. both examined the interaction between UL141 and the two TRAIL DRs. They found that UL141 directly binds to the ectodomain of TRAILR1 and TRAILR2 and that it has a higher affinity for TRAILR2. Nemčovičová et al. investigated the interaction in more detail by generating a 2.1 Å resolution crystal structure of the UL141–TRAILR2 complex. Interestingly, although UL141 shows no structural homology to TRAIL and has an immunoglobulin fold rather than a TNF fold, the structure revealed that the protein seems to have evolved binding motifs (for example, the TNF-specific hydrophobic motif) which mimic those motifs that are integral for the interaction between TRAIL and TRAILR2 and for other TNF–TNF receptor interactions.

So how does UL141 interfere with signalling from TRAIL DRs? Smith et al. found that fibroblasts infected with wild-type HCMV had reduced surface levels of TRAILR2 but higher total cellular levels than fibroblasts infected with a virus lacking UL141. This suggested that UL141 sequesters TRAIL DRs in an intracellular compartment. Indeed, when UL141 was co-expressed with TRAILR2, this DR was restricted mainly to the ER, where UL141 is known to localize. Notably, UL141 also modulates the immune response by downregulating the surface expression of CD155 (also known as PVR; a ligand for a natural killer (NK) cell receptor), and the structural analysis by Nemčovičová et al. showed that UL141 binds this receptor using a distinct binding site.

Finally, Smith et al. assessed the physiological effects of UL141-mediated reduction of TRAIL DR cell surface expression. Consistent with a role for TRAIL DRs in promoting apoptosis, fibroblasts infected with HCMV lacking UL141 were significantly more sensitive to apoptosis than those infected with UL141-expressing virus. Moreover, cells expressing UL141, as well as cells in which TRAIL-mediated functions were blocked, were significantly less sensitive than control cells to killing by NK cells. Together, these findings suggest that UL141 promotes HCMV survival by blocking TRAIL DR surface expression, thus inhibiting apoptosis and NK cell-mediated killing of the host cell.

These two studies add to the growing list of viral proteins that interfere with TNF signalling, and highlight UL141 as one of only two examples (together with herpesvirus entry mediator (HVEM)) of an immunoglobulin-fold-containing protein that binds to a TNF receptor.