recombination

Recombination between cellular and viral RNA produces a pathogenic virus

11 May 2010 by Vincent Racaniello

Bovine viral diarrhea virus is an economically important animal pathogen that may cause a fatal gastrointestinal disease in beef and dairy herds. Infection of a fetus with this virus during the first trimester leads to the birth of animals that are persistently infected for life. Some animals remain healthy, while others develop severe mucosal disease. The lethal outcome is a consequence of RNA recombination that produces a cytopathic virus.

Pathogenicity of bovine viral diarrhea virus is associated with the synthesis of a the viral protein NS3. This protein is not produced by the noncytopathic virus that persistently infects cows for life. Absence of the protein is due to failure to cleave the precursor of NS3, called NS2-3. In cells infected with the cytopathic, disease-causing virus, NS3 is produced because the virus has acquired an extra cleavage site. This difference is illustrated in the diagram (click for a larger view).

The extra cleavage site in the viral protein is acquired when the viral RNA of the noncytopathic virus recombines with cellular RNA. This exchange of sequence probably occurs when the enzyme copying the viral RNA briefly switches to a cellular RNA, and then back to the viral RNA. The result is a copy of the viral RNA into which a cellular sequence has been inserted.

The cleavage site for NS3 can be created in several ways. One of the most frequent is the insertion of a cellular RNA sequence coding for ubiquitin (UCH in the diagram). This small protein can be cleaved by members of a family of cellular proteases (proteases are enzymes that cut proteins). The insertion of ubiquitin leads to cleavage of NS2-3 and the production of NS3. The recombinant viruses replicate faster than noncytopathic viruses and cause disease in cattle. Why pathogenicity is associated with release of the NS3 protein, which is involved in viral RNA synthesis,Â is not known.

The production of pathogenic pestiviruses by recombination with cellular RNA is another illustration of the many unexpected pathways of viral evolution.

Meyers, G., Tautz, N., Dubovi, E., & Thiel, H. (1991). Viral cytopathogenicity correlated with integration of ubiquitin-coding sequences. Virology, 180 (2), 602-616 DOI: 10.1016/0042-6822(91)90074-L

A plant virus that switched to vertebrates

26 April 2010 by Vincent Racaniello

Viruses can be transmitted to completely new host species that they have not previously infected. Usually host defenses stop the infection before any replication and adaptation can take place. On rare occasions, a novel population of viruses arises in the new host. These interspecies infections can sometimes be deduced by sequence analyses, providing a glimpse of the amazing and unpredictable paths of virus evolution. One example is a plant virus that switched hosts and infected vertebrates.

Circoviruses infect vertebrates and have small, circular, single-stranded DNA genomes. Nanoviruses have the same genome structure, but infect plants. The genes encoding one of the viral proteins – called the Rep protein – appear to be hybrids, and share significant sequence similarity. They also exhibit homology with a protein encoded by caliciviruses, which are RNA viruses that infect many different vertebrates.

Analysis of the viral DNA sequences suggests that two remarkable events occurred during the evolution of circoviruses and nanoviruses. Not long ago, a nanovirus was transmitted from a plant to a vertebrate. This event might have occurred when a vertebrate fed on an infected plant. The virus adapted to vertebrates, and the circovirus family was established. After the host switch from plants to vertebrates, recombination took place between the circovirus and a vertebrate calicivirus. A reverse transcriptase probably converted the circovirus RNA genome to DNA to allow recombination to occur.

Similar interspecies transmission events have lead to outbreaks of human disease. One notable example is the transfer of simian immunodeficiency virus-1 from chimpanzees to humans. This host switch event, which is believe to have occurred in the early part of the 20th century, lead to the current AIDS pandemic.

Gibbs, M. (1999). Evidence that a plant virus switched hosts to infect a vertebrate and then recombined with a vertebrate-infecting virus Proceedings of the National Academy of Sciences, 96 (14), 8022-8027 DOI: 10.1073/pnas.96.14.8022

The trajectory of evolution

11 June 2009 by Vincent Racaniello

Scientists and philosophers have long debated the trajectory of evolution. Some of the questions they consider include: is there a predictable direction for evolution, and if there is, what is the pathway? Are there evolutionary dead ends?

Viruses are excellent subjects for the study of evolution: they have short generation times, high yields of offspring, and prodigious levels of mutation, recombination, and reassortment. Furthermore, selection pressures can be readily applied in the laboratory, and may be often be identified in nature.

When studying evolution of viruses, it is important to avoid judging outcomes as ‘good’ or ‘bad’. Anthropormorphic assessments of virus evolution come naturally to humans, but concluding that viruses become ‘better adapted’ to their hosts, for example, fails to recognize the main goal of evolution: survival. Or, in the case of the non-living viruses, existence.

Evolution does not move a viral genome from simple to complex, or along a trajectory aimed at perfection. Change comes about by eliminating those viruses that are not well adapted for the current conditions, not by building something that will fare better tomorrow.