Viruses Defined by the Position of the Virosphere within the Replicator Space

Abstract

Originally, viruses were defined as miniscule infectious agents that passed through filters that retain even the smallest cells. Subsequently, viruses were considered obligate intracellular parasites whose reproduction depends on their cellular hosts for energy supply and molecular building blocks. However, these features are insufficient to unambiguously define viruses as they are broadly understood today. We outline possible approaches to define viruses and explore the boundaries of the virosphere within the virtual space of replicators and the relationships between viruses and other types of replicators. Regardless of how, exactly, viruses are defined, viruses clearly have evolved on many occasions from nonviral replicators, such as plasmids, by recruiting host proteins to become virion components. Conversely, other types of replicators have repeatedly evolved from viruses. Thus, the virosphere is a dynamic entity with extensive evolutionary traffic across its boundaries. We argue that the virosphere proper, here termed orthovirosphere, consists of a distinct variety of replicators that encode structural proteins encasing the replicators' genomes, thereby providing protection and facilitating transmission among hosts. Numerous and diverse replicators, such as virus-derived but capsidless RNA and DNA elements, or defective viruses occupy the zone surrounding the orthovirosphere in the virtual replicator space. We define this zone as the perivirosphere. Although intense debates on the nature of certain replicators that adorn the internal and external boundaries of the virosphere will likely continue, we present an operational definition of virus that recently has been accepted by the International Committee on Taxonomy of Viruses.

Keywords: MGE; mobile genetic element; orthovirosphere; perivirosphere; replicator; virosphere; virus; virus classification; virus definition; virus taxonomy.

FIG 1

Viruses, their cycles of replication and expression, and the six monophyletic realms. The Baltimore classes (I to VII) (25) are shown in open boxes along with the major attributes characteristic for each class. Gray boxes, corresponding to each of the six monophyletic realms, are aligned with the Baltimore classes with which the member viruses are affiliated based on the type of nucleic acid encapsidated into their virions. The host range of viruses in each realm is indicated with different shapes: circles for bacteria, triangles for archaea, and squares for eukaryotes. RdRp, RNA-directed RNA polymerase; RT, reverse transcriptase.

FIG 2

The virosphere—orthovirosphere and perivirosphere—within the replicator space. Tobacco mosaic virus (TMV) was the first replicating noncellular mobile genetic element (MGE) to be called “virus” and hence occupies the center of the debate of how viruses should be defined. Shortly after the discovery of TMV, other MGEs, such as enterobacteria phage PRD1, “phage lambda,” and phage ΦX174, were discovered that, in some aspects, are fundamentally different from TMV but yet were quickly accepted as “viruses” by the scientific community. Hence, they are located close to TMV as “quintessential” viruses although they are phylogenetically unrelated. Today, these viruses are members of distinct, polyphyletic viral realms, with each relative of the quintessential viruses sharing, losing, or gaining certain properties that shape the debate on what constitutes a “virus.” In the three-dimensional space of the virosphere, i.e., the space that is occupied by all MGEs, a fuzzy (red dotted) line can be drawn at arbitrary places that separate the orthovirosphere (bona fide viruses as per any established definition; orange) from the perivirosphere (virus-like MGEs; blue). The placement of the fuzzy line is determined by the scientific community’s consensus about the nature of a particular MGE. For instance, there is no controversy about herpes simplex virus 1 (HSV-1) being a “virus,” and there is little controversy about viroids and virusoids not being viruses. The line is fuzzy because MGEs exist that have or lack properties that make their placement challenging. For instance, hepatitis delta virus 1 (HDV-1), accepted as a “virus” by many (123), shares many properties with viroids and virusoids and hence is considered not to be a “virus” by others. GTA, gene transfer agent; HIV-1, human immunodeficiency virus 1; HK97, Escherichia coli phage HK97; ICE, integrative and conjugative element; LTR, long-terminal repeat; MS2, Escherichia coli phage MS2; PCV-2, porcine circovirus 2; PFV2, Pyrobaculum filamentous virus 2; RCR, rolling-circle-replicating; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VARV, variola virus. For simplicity, organismal and organellar genomes have been omitted from the cubical extravirospherical replicator space.

FIG 3

Evolutionary relationships among mobile genetic elements (MGEs) and between MGEs and their organismal hosts. Shown is a simplified depiction of the organismal evolutionary tree of life (inspired by references and 250) outlining the two major supergroups of cellular life, Bacteria and Archaea, with eukaryotes evolving from (heimdallarchaeote) archaea. All organismal life relates to a last universal common ancestor (LUCA) located at the bottom of the trunk of the tree. In contrast, MGEs, the occupants of the virosphere, are polyphyletic and hence do not have a single LUCA. Hence, several individual evolutionary trees of MGEs need to be superimposed onto the cellular tree of life through the relationships of individual MGEs and their cellular hosts (here illustrated through the six currently establishes realms of viruses within the orthovirosphere and the less-defined space of the perivirosphere). Tobacco mosaic virus (TMV), enterobacteria phage PRD1, “phage lambda,” Pyrobaculum filamentous virus 2 (PFV2), and phage ΦX174—among the first representatives of viral realms Riboviria, Varidnaviria, Duplodnaviria, Adnaviria, and Monodnaviria, respectively, and hence at the center of Fig. 1 as a starting point to operationally define “viruses”—occupy the periphery of the actual evolutionary cellular and MGE trees. For instance, phages PRD1, lambda, and ΦX174 as well as HK97 and MS2 all infect gammaproteobacterial Enterobacteria such as Escherichia coli and hence are located at the same location on the cellular tree of life albeit being completely unrelated to each other. On the other hand, TMV infects solanacean plants and hence is placed on the archaeplastid subbranch of Eukaryota, whereas human viruses (e.g., hepatitis delta virus 1 [HDV-1], herpes simplex virus [HSV-1], human immunodeficiency virus 1 [HIV-1], severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], and variola virus [VARV]) are located at the same location on the ophistokont subbranch of Eukaryota. Porcine circovirus 2 (PCV-2) infects mammals different from humans (suids) and hence is located closely to the human viruses. Virus realms are depicted as branching lines with fading termini, as it is currently unclear when in evolutionary history each lineage began and which cellular tree branches they actually penetrate. For instance, duplodnaviriads infect bacteria, archaea, and mammalian eukaryotes, and hence it is likely that they occupy most of the cellular tree of life. On the other hand, adnaviriads have thus far only been found in a small number of crenarcheotes and, hence, here only occupy part of the cellular tree of life.