The Evolution of Viruses - Zhdanov, V. M. 1990

Special Section
Paramyxoviruses

Paramyxoviruses, along with orthomyxoviruses, Rhabdoviruses, Bunyaviruses, and Arenaviruses, form a well-defined group of negative-sense single-stranded RNA Viruses. Their RNA is non-infectious and does not directly encode Protein Synthesis. The latter is preceded by the synthesis of a complementary strand that Functions as mRNA. Regardless of whether The Genome is continuous or segmented, each Gene is transcribed individually, possessing its own reading frame and regulatory region. Naturally, the Synthesis of the complementary strand(s) acting as mRNA is driven by a virus-specific polymerase contained within the virions. This same polymerase (or polymerase complex) synthesizes the full-length complementary RNA strand(s), which serves as a template for progeny RNA Synthesis.

These are the general features shared by these 5 virus groups that distinguish them from viruses of any other group. Differences also exist among them. Paramyxoviruses and rhabdoviruses have a continuous genome, in arenaviruses it consists of two segments, in bunyaviruses — of 3, and in orthomyxoviruses — of 7–8. Their overall size also varies: up to 4.6x10⁶ for rhabdoviruses, up to 4.8х10⁶ for arenaviruses, 5x10⁶ for orthomyxoviruses, and 5х10⁶–7x10⁶ for paramyxoviruses and bunyaviruses. Virion dimensions for spherical forms are 90–100 nm (bunyaviruses), 80–120 nm (orthomyxoviruses), 110–130 nm (arenaviruses), and 140–150 nm (paramyxoviruses); bullet- or rod-shaped rhabdovirus virions measure 50–90x130x380 nm. The nucleocapsid (ribonucleoprotein) is packaged with helical Symmetry. The host range includes warm-blooded animals (paramyxo-, orthomyxo-, and arenaviruses), as well as warm-blooded animals or Blood-sucking vectors (bunya- and rhabdoviruses). A large subset of the latter viruses infects plants and is transmitted by sucking insects. Morphologically similar viruses have also been described in plants, along with morphologically similar non-enveloped structures (see Chapter 14).

The similarity in the core CHARACTERISTICS OF THE 5 negative-sense RNA virus groups suggests a common or closely related origin. Given their host range—higher animals, plants, and vector insects (hematophagous or sap-sucking)—it is reasonable to hypothesize that these viruses emerged no earlier than 200–300 million years ago, and possibly significantly later. At the same time, at least one of the groups under consideration has managed to colonize vast ecological niches (higher animals, higher plants).

Several hypotheses can be put forward regarding THE ORIGIN OF negative-sense single-stranded RNA viruses. It is possible that they arose from Cellular Structures and subsequently diverged to form the 5 groups existing today. They may not have shared a single common ancestor; instead, similar structures could have arisen independently and then evolved along separate paths. However, we find it more likely that they originated from double-stranded RNA viruses—representing the autonomous RNA genome's first line of defense against cellular Nucleases. Yeast killer systems are Examples of such structures. The next stage was represented by fungal viruses, which possess a double-stranded RNA genome and their own RNA polymerase. Notably, these viruses could have emerged very early, around the time primitive eukaryotic forms—Fungi—first appeared. Reoviruses may have formed one of the main evolutionary branches of primitive double-stranded RNA viruses. Their Abundance and occupation of a broad ecological niche (higher animals, higher plants, arthropod vectors) point to the realization of such an evolutionary pathway. Yet another direction could have been a reversion to a single-stranded RNA genome, since such a genome is well protected from cellular nucleases within the virion, while double-stranded RNA still serves as the replicative form. Naturally, with a virion-associated polymerase present, the genome had to be a minus-strand, which was indeed the path taken in this evolutionary Lineage. Incidentally, none of the single-stranded RNA viruses with a virion polymerase possesses a positive-sense genome, with the obvious exception of Retroviruses.

In accordance with this hypothesis, the existing 5 groups of negative-sense genomic RNA viruses hardly shared a single common ancestor; rather, there were several, albeit evolutionarily closely related ones. This assumption is supported by the limited variations in genome molecular weight (from 4x10⁶ to 7x10⁶). There are no "dwarfs" among them like small RNA-containing phages (with a genome mass of about 10⁶). The Genome Size does not exceed 7x10⁶–8x10⁶ across all Introduction/7.html">RNA-containing Viruses, even reoviruses, for which the value of 15x10⁶–16x10⁶ actually represents a "half" size, since Genetic information is encoded on only one RNA strand.

However, the actual evolutionary trajectory traversed by these viruses (specifically paramyxoviruses) may have been considerably more complex. This is supported by data on The production of Monoclonal Antibodies against the measles virus F protein. Out of 11 such antibodies, 3 reacted with a protein (molecular weight 79,000) from HeLa Cells whose synthesis was induced by other paramyxoviruses, heat Shock, kanamycin, etc. This protein is known as a stress protein [Sheshbezadaran H., Norrby E., 1984]. The cited authors view this phenomenon as a potential basis for autoimmune reactions, whereas we raise the question of whether this reflects an evolutionary Homology of cross-reacting Proteins or is rather a case of molecular convergence.

Following these considerations on the origin of negative-sense RNA viruses, let us examine the evolution of paramyxoviruses, first recalling some necessary Background information on them [Zakstelskaya L. Ya., Zaydes V. M., 1982; Matthews R., 1982].

As already noted, the paramyxovirus genome is a single-stranded negative-sense RNA with a Molecular Weight of 5x10⁶–7x10⁶ and a sedimentation coefficient of 45–57S. Some virions (up to 30%) contain plus-strands, which should be regarded as the result of unbalanced synthesis. A poly(A) tail is present at the 5'-end of the molecule. While virion RNA is non-infectious, the ribonucleoprotein possesses infectious properties. Messenger RNAs are heterogeneous and sediment at 18–35S [Kingsbury D. et al., 1978].

The measles virus P gene contains 1,657 NUCLEOTIDES and can encode a protein consisting of 507 amino acid residues. In reality, however, it encodes two proteins, the second of which (C), comprising 186 amino acid residues, is synthesized from an overlapping reading frame [Bellini W. et al., 1985]. This phenomenon also occurs in other paramyxoviruses, notably Sendai virus (Fig. 22). It is possible that the C protein plays a specific role in the putative nuclear Replication phase of the measles virus. The internal NP, P, and M proteins of paramyxoviruses (Sendai virus) are arranged as follows: NP proteins are distributed along the entire RNA strand, the P protein forms discrete clusters at various sites along the nucleocapsid, while the M protein forms aggregates along the nucleocapsid in the Cytoplasm of infected cells, and surrounds the nucleocapsid in virions [Portner A., Murti K., 1986].

Class="center">

Fig. 22. Genome Structure of Sendai virus. THE POSITION OF the positive-sense leader sequence (l+) is indicated; E, I, and S denote the terminal, intergenic, and start mRNA sequences, respectively.

Among the 5–7 virion proteins with molecular weights ranging from 35,000 to 200,000, we note the NP nucleoprotein (60,000), the RNA-dependent RNA polymerase (P and L proteins with molecular weights of 75,000 and 160,000, respectively), internal membrane M proteins (40,000–43,000), hemagglutinin-neuraminidase HN (67,000–76,000), and the Cell Fusion and hemolysis factor F (55,000–60,000). Modern data indicate the presence of 5 proteins in virion cores: NP0 (68,000), NP1 (58,000), NP2 (52,000), which are associated with 50S RNA, along with L (240,000) polymerase and P (84,000) phosphoprotein. Four proteins are located in the envelopes: F1 + F2 (53,000 + 12,000), HN (72,000), and M (40,000) [Jambou R. et al., 1985].

In the respiratory syncytial virus, downstream of the promoter, the genes are arranged in the following order: 3'-IC—IB—N—P—M—IA—G—F—22,000—L-5'. The N gene encodes the nucleoprotein, G and F encode surface Glycoproteins, M encodes the membrane protein, and P and L encode the polymerase complex. The genes are separated by 1–52 nucleotide-long sequences; the Functions of the remaining genes are not fully understood. For comparison, we present the gene arrangement in rhabdoviruses and two genera of paramyxoviruses. In rhabdoviruses (vesicular stomatitis virus): N—NS—M—G—L; in paramyxoviruses (Sendai virus and human parainfluenza virus type 3): NP—P + C—M——F—HN—L; RSV: NP—P+Y—M—F—SH—HN—L.

Overall, despite the differences between ortho- and paramyxoviruses (specifically, a segmented genome in the former and a continuous one in the latter), their protein profiles are remarkably similar, including outer envelope glycoproteins that are cleaved into subunits and subsequently linked by Disulfide Bonds to assume their final conformation. The virion Morphology and, in broad outlines, the reproductive cycle are also alike.

Paramyxoviruses are relatively few in number and exclusively infect higher animals—mammals and birds. They comprise three genera: typical paramyxoviruses (12 species), morbilliviruses (4 species), and pneumoviruses (3 species). Their evolution can be visualized as dissemination across various host species, with some causing acute infections and others chronic or persistent infections.

Antigenic relationships among avian and porcine paramyxoviruses are illustrated in Fig. 23 [Lipkind M. et al., 1986].

Uniting rhabdo- and paramyxoviruses by origin, A. D. Altshtein and N. V. Kaverin (1980) suggested that rhabdoviruses originated from plant viruses, with their host range expanding only later to encompass insects and subsequently vertebrates. The acquisition of The ability to replicate in respiratory tract cells led to The Emergence of paramyxoviruses.

There are grounds to consider ortho- and paramyxoviruses evolutionarily related. This is evident from comparative data indicating homology between certain genes of Sendai virus and Influenza A virus [Giorgi C. et al., 1983] (the degree of homology is indicated by varying letter sizes).

Sendai virus genes:

NP; agacaggattTTAGGGTcAAAGtATc CACccTgA GGagCA GGttcCAg ACCC.

P/C; TAAGAAAAACTTAGGGTgAAAGttcATcCAC TgA tcGGctCA GG CAaggccacACCC,.

M; TAAGAAAAACTTAGGGTgAAA GaaÄTttCACc TaAcaGGcgCAatGG CAgatatctat.

Influenza virus NP gene:

AGcAAAA gcAGGGT atata ATctCAC TgAgt GG CA tcCA tatc.

At the same time, certain paramyxovirus genes bear the "hallmark" of cellular origin, manifested as a distinctive antigenic mimicry identified in the Nucleoproteins of measles virus and respiratory syncytial virus [Norrby E. et al., 1986].

The Main criteria for distinguishing genera are the presence of neuraminidase activity (paramyxoviruses), nucleocapsid size (morbilliviruses), and other structural features (pneumoviruses). Morbilliviruses also form a group of serologically related viruses. It is also worth noting that some of these viruses are polypathogenic. For example, parainfluenza virus type 3 infects humans, sheep, and cattle; parainfluenza virus type 5 infects monkeys, dogs, and birds; and parainfluenza virus type 1 infects humans and mice. (This refers not to laboratory experiments, but to natural epidemic and epizootic processes.) In addition, certain animal-affecting paramyxoviruses can also cause diseases in humans. For instance, Newcastle disease virus, which affects chickens, can cause transient Conjunctivitis in humans.

Fig. 23. Antigenic relationships among paramyxoviruses. Arrows point from a virus whose antiserum inhibits another virus toward a virus whose antiserum does not inhibit it.

I — inter-immune sera; II — sera from convalescent animals; 1 — significant relationship; 2 — moderate relationship; 3 — weak relationship; 4 — one-way relationship.

It is also worth noting that among the animals affected, those domesticated by humans (cattle, dogs, chickens) predominate, alongside mice that inhabit human dwellings. Therefore, this group of viruses should be considered a relatively late "emergence"—dating back no more than 10,000 years—while the viruses affecting humans appeared much later. The derivative origin of human paramyxoviruses is evidenced by the pronounced conservation of the HN genes in bovine and human viruses [Coelingh K. et al., 1986].

Let us examine the Evolution of the measles virus, which belongs to the genus Morbillivirus within the family Paramyxoviridae. Along the way, we will Touch upon the subject of latent viral infections. Our focus will not be on the potential Phylogenesis of the pathogens themselves, but rather on the conditions of their emergence and evolution at various stages of human social development.

The Characteristic Features of all infections in this group include ease of transmission, high human susceptibility, acute clinical course, a relatively short contagious period (ranging from a few days to a few weeks), the absence of a carrier state, and robust post-infection Immunity. All of this indicates that such infections could not have existed during the primitive communal era, when people lived in scattered groups with little contact with one another or with other tribes. The emergence of such an infection would have led to the illness of the entire tribe within a short period, after which the pathogen would inevitably have perished, even if it possessed high stability (which is not characteristic of pathogens in this disease group). Neither a nomadic lifestyle nor the transition to a settled life with relatively isolated tribes and small populations provided the necessary conditions for the survival of parasitic species in this category.

The validity of these Conclusions is best illustrated by the Epidemiology of measles. Measles is one of the most widespread childhood diseases, and prior to the introduction of mass immunization with the measles vaccine, virtually every person contracted this infection during childhood. The high contagiousness of measles patients and the airborne route of transmission mean that in modern society, individuals are repeatedly infected throughout their lives, starting in early childhood. Due to absolute susceptibility, a child falls ill upon the very first infection, which occurs in childhood. The contracted infection establishes lifelong, robust immunity, preventing reinfection. This leads to the Conclusion: the more crowded the population and the more intense the social interaction, the earlier in life the disease occurs. In densely populated cities, children typically contract measles by the age of 3–4. In rural areas, particularly those isolated from railways and other transport routes, the majority of measles cases shift to older age groups. Finally, in regions isolated from the rest of the world, measles is not exclusively a childhood disease, and outbreaks introduced from outside affect both children and adults alike.

A classic example is the measles epidemics in the Faroe Islands during the 19th century. The first epidemic occurred after a 65-year hiatus, during which not a single case of measles was recorded on the islands. In March 1846, a person arrived on one of the islands who had been in contact with a measles patient prior to departure. A few days after arrival, this person developed measles, triggering an epidemic that affected the entire population of the islands. The epidemic subsided once no susceptible individuals remained among those in contact with the sick. Following this, the islands remained free of measles for 16 years. A new epidemic broke out in 1882 after the virus was introduced by an infected traveler arriving on the island. This time, the infection affected individuals up to the age of 16, as the rest of the population had contracted the disease during the previous epidemic. Another 13 years later, in 1875, measles was once again "imported" from the mainland, and on this occasion, the epidemic affected children only up to the age of 13. Thus, as ties with the mainland strengthened, the introduction of measles to the islands became more frequent, and the infection reverted to being exclusively a childhood disease. However, measles could not sustain itself permanently in a population of 7,000, and each new epidemic arose solely As a result of the pathogen being reintroduced.

This example demonstrates that measles-like infections can only exist at an advanced stage of human social development, characterized by The formation of large states with vast territories, massive populations, and developed transport networks. High population density and developed transport ensure the spread of the infection across the territory, while vast territory and a significant population size mean that by the time the epidemic spreads from one end of the region to the other, a substantial number of susceptible children are born and grow up at the original site of the outbreak. In this way, the measles epidemic propagates in waves, ensuring the continuity of the epidemic process.

Until recently, the measles virus was poorly understood and appeared to "stand alone" among viruses, lacking closely related counterparts. Today, however, several viruses are known that share A number of biological properties with the measles pathogen (such as the canine distemper virus and other related viruses in this group).

Canine distemper presents in puppies as an acute septic infection, and recovery may be followed by a prolonged carrier state. In some animals, particularly adult dogs, it can manifest as a long-term latent infection. The virus is transmitted via mucosal secretions, and infection occurs either alimentary or through direct contact between animals; notably, offspring are frequently infected by their mothers, who act as latent virus carriers.

Sequencing studies of the measles and canine distemper virus genomes have revealed a high degree of homology. In particular, this applies to the nucleoprotein gene, which contains regions of high (77%), moderate (59%), and low homology [Rozenblatt S. et al., 1985]. Cytomegalovirus disease most commonly presents as a latent infection, though in young children it frequently manifests as Pneumonia or nonspecific septic illness. Measles, by contrast, always presents with a clinically distinct picture and an acute course, culminating in lifelong, robust immunity.

We have drawn a parallel between these three infections not to claim that human cytomegalovirus disease "originated" from canine distemper, or that measles is the product of its further evolution. Rather, this parallel is drawn to illustrate a highly probable evolutionary pathway for the pathogens of many human infections. While smallpox represents the adaptation of an animal pathogen to the human Organism accompanied by The Development of an acute infection, measles apparently evolved in two stages: first, the canine parasite adapted to the human organism, with the infectious process retaining the same characteristics as in animals—or perhaps becoming even more latent; subsequently, an acute smallpox-type infection developed, which modern measles represents. One can only speculate as to why this evolution was two-tiered. This may have occurred because, although dogs are social animals, contact between different packs was likely irregular. Consequently, the canine distemper virus could not have survived in these animals without acquiring the ability to persist latently within their bodies for extended periods. Naturally, it retained these traits upon adapting to the human organism, evolving only later into the measles virus—an acute infection that prompts The Human Body to develop lasting post-infection immunity, thereby precluding any carrier state or prolonged latent persistence of the virus.

This could have occurred either through the gradual accumulation of minor changes or via Mutations. Measles could only emerge at a time when human interaction became intensive across vast territories encompassing many millions of people, since under any other conditions the reservoir of susceptible individuals would have been insufficient to sustain the pathogen. It must be remembered that people contract measles only once in their lifetime; furthermore, airborne transmission and high susceptibility mean that every epidemic of this disease "clears out" the susceptible population layer almost to zero. Therefore, measles can only survive by continuously "roaming" across a large territory. When it eventually "returns" to an area where an epidemic previously occurred, a sufficient number of newly born and growing children have formed a noticeable susceptible population layer by that time. However, this requires large territories with a sufficiently dense population and sustained, constant interaction between communities, allowing the measles virus to "make the rounds" of the territory within a period of no less than 3–5 years.

The evolution of measles proceeded in such a way that it increasingly became an endemic childhood infection in densely populated Regions of the globe, causing periodic, regularly recurring epidemics while remaining an "imported" infection for less populated and isolated territories, where all age groups are affected. Today, measles is a textbook infection of developed, civilized society. There is only one way to halt its spread: the mass immunization of children with an effective vaccine. This measure made it possible to reduce measles incidence by a factor of 9–10 almost immediately. Further research into the effectiveness of measles immunization must determine whether this infection will be eradicated, much like smallpox, or whether its incidence will merely be maintained at a sufficiently low level. In our view, the goal of eradicating measles is entirely realistic, but it demands intensive scientific development.

Evidently, other human infections followed a similar path—specifically those caused by paramyxoviruses of 4 serotypes, as well as the respiratory syncytial virus. Their evolution is far from complete, and two of them (parainfluenza virus 3 and respiratory syncytial virus) have become a genuine scourge, particularly for children.