How the largest virus ever discovered rose from the dead and taught us a few a lessons about viral latency
By Asu Erden
The first giant DNA virus was discovered only 10 years ago and astounded the scientific community due to its implications for viral biology. How could a virus that lied dormant for thousands of years still be infectious? Last week, scientists from the National Centre of Scientific Research (CNRS) in France published their findings in the Proceedings of the National Academy of Sciences about the 30,000 year-old virus they uncovered from the deeper layers of the Siberian soil. This giant DNA virus, called Pithovirus sibericum, is the largest one ever found. It does not infect humans but Legendre et al. have shown that it can parasitise amoebae.
It was hitherto believed that giant DNA viruses belonged to two widely different families: the Megaviridiae and the Pandoraviruses. The former have smaller particle sizes and genomes and replicate in the host cell’s cytoplasm, which means that they do not need to hijack the cell machinery to make copies of themselves. The Pandoraviruses, on the other hand, have larger particle sizes and genomes and need to enter the host nucleus to replicate. The newly discovered Siberian virus belongs to a new category, called Pithoviruses, that combines features from both of the formerly described giant virus families. It exhibits a large particle size, a small genome, and has entirely cytoplasmic replication. This means that the biology of giant viruses is much more diverse than previously imagined. It seems that many different features can allow a virus to survive freezing temperatures and to rise still fully functional after thirty millennia of hibernation.
While scientists keep virus stocks at freezing temperature for long-term storage, the idea that viruses can survive for tens or hundreds of millennia in ice remains a contentious issue in the field. In their study, Legendre et al. combined microscopy techniques and infection assays in amoebae to identify putative DNA viruses from Siberian deep soil samples. Using amoebae as bait for putative pathogens from soil samples, they observed that these eukaryotic organisms started to die. This is when Legendre et al. knew they were onto something. The infection assay allowed them to identify and characterise Pithovirus sibericum as a rod-shaped virus of approximately 1.5 μm making it bigger than many bacteria. Infection “symptoms” within the amoebae appeared after 4 to 6 hours. A few hours later, viral particles were ready to bud out of their host cells and continue their infectious cycle.
The French team was somewhat helped by the geochemical and geophysical properties of the Siberian deep soil, also called permafrost. Indeed, this frozen soil layer has a neutral pH and provides an anaerobic environment to the organisms it imprisons. Previous studies have shown that these non-fluctuating frozen conditions are ideal for long-term DNA preservation. As such, the credible threat posed by the thawing of such viruses remains unclear. However, it seems like this undead prehistoric pathogen can teach us a few lessons about viruses of current relevance to public health.
Many of the viruses infecting humans have a latent phase during which they continue to infect cells but do not replicate and therefore do not circulate within their hosts. They therefore remain invisible to our immune system and are extremely difficult to monitor. Such viruses include the varicella zoster virus (VZV) responsible for chicken pox during childhood and shingles later in life, cytomegalovirus, which infects over 60% of us, and most infamously the human immunodeficiency virus (HIV).
While the discovery of P. sibericum from thawed Siberian permafrost is a relevant harbinger of the many long-term destructive effects of global warming, it should also be lauded as a reminder of the ongoing scientific challenge that viral latency poses to researchers, physicians, and most importantly patients. Just like the features that allow some pathogens to survive for thousands of years in the ice before they are unleashed into the wild, the precise factors that lead to the reactivation of a latent virus remain elusive. As Legendre et al. put it, “an entire world of viruses [remains] to be unraveled.” Let this new viral discovery be a humbling memo that there is still plenty that we do not understand about these microorganisms and that they will continue to fascinate and challenge us for years to come.