Deltaviruses Use a Trojan Horse Method to Spread

Viruses are crafty and can employ different strategies to spread. One approach involves a virus relying on another “helper” virus to infect. A classic example is hepatitis delta virus (HDV), which hijacks hepatitis B virus surface glycoproteins to enter cells.

In recent years, scientists have discovered many HDV-like deltaviruses in animals. While helper viral glycoproteins play a role in infectivity, the broader nature of deltavirus–helper virus interactions remained largely unresolved. This motivated researchers at the Institute of Molecular Genetics of Montpellier (IGMM) and the French National Center for Scientific Research (CNRS) to take a closer look at this relationship.

Their findings, published in Cell, revealed a previously unrecognized mode of viral transmission.¹ Instead of hitchhiking on the surface of helper virus glycoproteins to enter cells, deltaviruses take a page out of an ancient Greek strategy—the Trojan Horse. Here, deltaviruses can package themselves inside another virus particle as a vehicle to spread and enter other cells. These findings reveal a novel viral transmission route and shed insight into how deltaviruses spread to different tissues.

The researchers first infected murine cells with rodent deltavirus (RDeV) and then introduced a second infection with vesicular stomatitis virus (VSV). The team had previously shown that this deltavirus can replicate and be packaged within the helper virus’s glycoproteins to form infectious particles.²

They observed the characteristic bullet-shaped VSV virions, smaller RDeV particles, and a surprising third population in the cellular supernatant. The team suspected that this third group might be a subset of VSV virions that was morphologically modified and might contain RDeV particles.

To investigate further, the researchers combined multiple imaging techniques, including electron microscopy and super-resolution microscopy, to confirm the presence of deltaviruses enclosed within the helper virus particles. Indeed, these deltaviruses were able to hitchhike inside VSV particles upon infection and gain entry to naive target cells. The researchers termed this mode of transmission as “viral Trojan Horse spread.”

But this phenomenon does not only occur in VSV models. The team expanded their analysis to include other helper virus families, such as herpesvirus and arenaviruses; cell lines derived from different organs, including the liver and kidney; and cells from various species. They observed a similar pattern of Trojan Horse packaging across these conditions. Notably, this mechanism was required for productive deltavirus infection.

Based on these findings, the researchers emphasized that more work is needed to identify these Trojan Horse particles in other viral settings. However, virologist Joe McKellar, a study coauthor at IGMM/CNRS, remarked in a press release, "It opens new questions about deltavirus tropism and evolution."