ince the dawn of microbiology, researchers have focused on pathogens that make us and our domesticated animals and plants sick. Because the onset of symptoms was the only way to know if specific viruses were present years ago, the most well-studied viruses are those that cause disease. But many viruses chronically infect humans without inducing disease, except perhaps in the very young, the very old, or the immunosuppressed.
In recent years, great leaps in genomic sciences have allowed researchers to detect viruses living in and on the human body—collectively called the human virome. Recent genomic explorations of human samples have revealed dozens of previously unrecognized viruses resident in our gut, lung, skin, and blood. Some of these newly identified viruses may underlie mysterious, unexplained diseases, but it is also possible that some of these viruses are harmless in most people, most of the time. Knowing how these newly discovered viruses affect humans will allow us to determine whether they are to be prevented, treated, ignored, or even encouraged.
A spectrum of viruses
Researchers can now identify viruses present using metagenomic analyses. This is achieved by comparing the genetic information from next-generation sequencing of clinical samples to the genomes of all known viruses. These include viruses that infect all branches of life, from humans to plants and bacteria. When a sample contains a previously identified virus, its genetic sequences can show upward of 80 percent similarity to viral sequences in public databases such as the National Center for Biotechnology Information and the European Nucleotide Archive. Such similarities are easily identified computationally.
More challenging are novel viruses whose DNA or RNA genome does not show a significant match to that of any known viruses. In these cases, researchers can translate viral genes into proteins in silico and computationally search for related viral protein sequences. Due to the redundancy of the genetic code and the need to maintain basic protein structures and active sites, protein sequences evolve at a slower rate than their genes, and are therefore recognizable over longer evolutionary time.
With this new ability to rapidly characterize viral genomes, data acquisition is outpacing our understanding of the viruses’ role in health and disease. A few years ago, only two polyomaviruses were known to infect humans. Using metagenomics approaches, researchers have identified 13 known human polyomavirus strains, and have linked some of these with diseases ranging from neurological or kidney damage in immunosuppressed transplant and AIDS patients to skin cancers.1 Most of these polyomaviruses infect a majority of people during childhood and are then silently carried until a weakened immune system unleashes them to wreak havoc.
Such occasional pathogenicity is typical of viral families found in humans. For example, some human papillomaviruses are found on the skin of most healthy adults and go unnoticed,2 while a few specific papillomaviruses can induce cervical or anal cancers (now preventable by early vaccination). Similarly, herpesviruses are nearly universal infections in adults, where they set up lifelong, symptom-free residence in neurons or cells of the immune system. Later in life or following immunosuppression, latent herpesviruses can reactivate and induce diseases ranging from cold sores to meningitis, lymphomas, or Kaposi’s sarcoma.
A rarely studied group of viruses called anelloviruses may claim the prize as the most common human viral infection; they can be detected in the blood of almost 100 percent of adults.3 Anelloviruses are transmitted very soon after birth and multiple strains can establish persistent viremia in the same person. Because of their level of genetic diversity—the highest of any viral family—anelloviruses may infect different tissues with different consequences. And as with papillomaviruses, it is conceivable that only a subset of anelloviruses may turn pathogenic.
Whether such common and persistent viruses affect health is still being sorted out. A frequent consequence of chronic and acute viral infection is immune overstimulation. The increasing concentration of anelloviruses seen in immune-suppressed individuals indicates that anelloviruses remain under immunological control and may therefore result in low-level chronic inflammation, known to result in myriad health problems. (See “Is It a Pathogen?” here.)
Despite this potential for affecting health, there is as yet no direct evidence that anellovirus infections are harmful. Their ubiquity and lack of acute pathogenicity does point to a long and successful coevolution with humans. Because anelloviruses infect nearly everyone, however, their potential impact on heath is particularly difficult to determine. Fortunately, scientists have recently discovered anelloviruses in monkeys and rodents, providing means to study these viruses’ pathogenicity in these animal models both in isolation and together with other common infections.
Beside the nearly universal blood-borne viruses described above, a cornucopia of other recently discovered viruses can be detected in respiratory and fecal samples of healthy persons, particularly children. These viruses include a growing number of astroviruses, parvoviruses, picornaviruses, picobirnaviruses, and others whose roles in health and disease also remain largely unknown. (See illustration here.)
This flood of new information regarding our virome indicates that, even when in perfect health, we are chronically infected by several types of viruses and often transiently infected by yet others. The perception that every human virus causes disease is therefore yielding to a much more complex biological reality….