Introduction

María-Carla SALEH1 and Félix AUGUSTO REY2

1 Viruses and RNAi Unit, Institut Pasteur and CNRS UMR 3569, Paris, France

2 Structural Virology Unit, Institut Pasteur and CNRS UMR 3569, Paris, France

Viruses are ubiquitous and have been a major driver in the evolution of life on Earth. Without viruses, life would certainly not be as we know it. Viruses are intimately linked to cells: invading a cell is mandatory for their reproduction and perpetuation in nature. The origin of viruses goes back to the origin of life, which emerged from primitive self-replicating nucleic acid molecules. The viruses that are mostly studied are those that cause disease in humans, animals or plants; however, disease-causing viruses are only an epiphenomenon in the global picture of the origin and evolution of life. Most viruses have evolved with their host and do not cause disease. Virus pathogenicity is most often the result of a change of context, such as the infection of new hosts in which they have not evolved and adapted. A good example is constituted by zoonotic viruses, such as the Ebola virus or the current coronavirus that is responsible for the COVID-19 pandemic, which are bat viruses and do not cause disease in their natural host.

Viruses have genome coding for all of the information required for their perpetuation in nature. Some viruses have very small genomes, while others have very large genomes. Baltimore introduced a classification of viruses into different groups, according to the way the viral genome produces messenger RNA once inside the cell, so that they can be translated into viral proteins (Baltimore 1971). There are seven virus groups according to this criterion, the simplest one being those in which the genome is a positive-sense, single-stranded RNA (+ssRNA) molecule (group IV in Baltimore's classification), which can be directly translated by the ribosomes in a cell. There is no transcription step required for group IV viruses, and the naked

genome is infectious, contrary to the RNA viruses in the other groups. One of the virally encoded enzymes is polymerase, which is capable of replicating the +ssRNA genome to make more progeny within the cell, as cells normally lack RNA-directed RNA polymerase activity. The replication of viruses in group IV takes place in the cytoplasm of the cell. Viruses in the other groups require the transcription of their genome in order to produce messenger RNA. Most of them encode viral polymerase, which needs to first transcribe the genome into messenger RNA to synthesize the viral proteins. In this case, the viral RNA is only infectious in association with the viral polymerase, and it is this complex that is delivered into the cytoplasm of the cell for a productive infection. After the initial transcription round, replication ensues - i.e. the synthesis of more genomic RNA - often using the same virally encoded polymerase, which has dual transcriptase and replicase activities - to be incorporated into new viral particles. For viruses in Baltimore groups VI and VII, the viral polymerase is a "reverse transcriptase" (RT). In group VI, the genome is a +ssRNA molecule that is not used as a messenger, but is transformed by RT into double-stranded DNA (dsDNA) that gains the cell nucleus and is integrated into the host cell genome to be transcribed by cellular polymerases. In the viruses in group VII, the genome is a DNA molecule that is maintained as an episome in the nucleus of the infected cell (i.e. it is not integrated into the host genome), in the form of a covalently closed circular DNA (cccDNA), like in the hepatitis B virus (HBV). This DNA genome is transcribed by cellular polymerase, and the RNA of full-length transcripts, called pregenomic RNA (prgRNA), is incorporated, along with RT, into newly formed viral particles. Once inside the particle, RT transforms the prgRNA into an incomplete double-stranded linear DNA genome that will be used to infect other cells.

This book provides several snapshots into the universe of viruses. They provide more detail on the replication of viruses in the most complex groups in the Baltimore classification. In Chapter 1, Lindsey M. Costantini and Blossom Damania discuss the replication of DNA viruses, which belong to Baltimore groups I (dsDNA viruses) and II (ssDNA viruses), as well as HBV (group VII). Most of these viruses replicate in the nucleus of the cell, but there are exceptions, such as the poxviruses. This chapter also highlights the specific features of some of the DNA viruses causing serious diseases in humans, notably the so-called oncogenic viruses, showing that some become integrated into the host genome, but others remain as episomes. In Chapter 2, Michelle M. Arnold, Albie van Dijk and Susana López analyze the life cycle of the viruses in group III, which have a double-stranded RNA genome that is always contained in an icosahedral proteinaceous capsid. This protein shell protects these viruses from the detection of their genomes by the cell. Indeed, dsRNA is not normally present in a cell, and therefore constitutes a pathogen-associated molecular pattern (PAMP) that is recognized by pattern recognition receptors (PRRs), which trigger the innate immune system of the host. For this reason, all RNA viruses have developed the means to isolate their replication compartments, in which transient dsRNA molecules form without being exposed to PAMPs.

In Chapter 3, Rachel Fearns describes the replication of viruses in group V, which have a negative-sense ssRNA genome in complex with a protein (termed "N" for nucleoprotein) that polymerizes all along the genome, and is associated with a large viral polymerase that is first used for transcription and then for replication. Some of these viruses have a segmented genome. While most of them replicate in the cytoplasm, some gain the nucleus for replication, for example the influenza virus. This chapter also describes the replication of one of the smallest viruses that infects humans, the hepatitis delta virus (HDV). Although it has a negative-sense ssRNA genome, it is so small that it does not code for a polymerase enzyme, nor for a capsid protein: it instead uses the capsid and envelope protein of a co-infecting HBV to propagate to other cells. For its replication, the HDV genome enters the nucleus and co-opts the cellular RNA polymerase II, which normally only transcribes DNA, for its own transcription and replication. This is a remarkable ability of this virus, to make cellular enzymes work in a different way for its own benefit.

Viruses can also hijack the metabolic pathways of a cell in order to make progeny and convert the cell into a virus-producing factory. During evolution, however, there is a constant arms race in which cells fight back - or more precisely, the whole organism fights back, sacrificing infected cells so that the infected organism survives as a whole. The PRRs detect foreign motifs (PAMPs) in the cell by using different mechanisms, in order to trigger a strong innate immune response that leads to the death and elimination of the infected cell. Viruses, in turn, have developed ways to counter this detection. In Chapter 4, Rachel Netzband and Cara T. Pager describe the extensive epigenetic modifications of viral nucleic acids that make them appear like cellular RNA and avoid or limit their detection by PRRs. On the contrary, it is in the virus' benefit to avoid killing its host. In Chapter 5, Carolina B. López describes the defective interfering particles generated by deletions, or other defects, in the replicated viral genome, which trigger the innate immunity of the cell. This delicate balance allows the virus to become persistent, with replication only at a basal level, protecting its host but ensuring its viability. This is another illustration of the constant interplay between viruses and cells during evolution, both mutually adapting in a race that is reminiscent of the Red Queen in Lewis Carrol's fiction Through the Looking-Glass (1871), constantly running to stay in the same place.

Evolution has been such that viruses have developed highly specific and sophisticated ways of interacting with their host. In Chapter 6, Matthew Phillips, Bria F. Dunlap, Megan T. Baldridge and Stephanie M. Karst illustrate the way enteric viruses co-opt the intestinal flora in order to augment their infectiveness. They bind to bacterial polysaccharides or other structures with high affinity and specificity, in order to use them as vehicles to efficiently reach their target cells in the intestinal epithelium. Similarly, viruses that are transmitted by arthropod vectors - notably insects or ticks - have evolved very efficient and specific ways of interacting with their vector in order to be transported and maximize their chances of finding new, uninfected hosts. Such an example is described in Chapter 7 by Swapna Priya Rajarapu, Diane E. Ullman, Marilyne Uzest, Dorith Rotenberg, Norma A. Ordaz and Anna E. Whitfield, who analyzed the interactions of plant viruses with their insect vectors. Some viruses have developed highly efficient ways to bind to an insect's mouth while it feeds on an infected plant, so that they can be transported to other susceptible plants. Some plant viruses replicate in their vector, and change insect behavior so that it is more attracted to uninfected plant hosts, thereby spreading the infection more easily. They further discuss the role of bacterial endosymbionts in the vertical transmission of viruses in the vector species, as a way of maintaining the virus even when...