A small infectious agent that is unable to replicate outside a living animal cell. Animal viruses infect animals and require animal cells as their host. Unlike other intracellular obligatory parasites (for example, chlamydiae and rickettsiae bacteria), animal viruses contain only one kind of nucleic acid, either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), but not both. They do not replicate by binary fission. Instead, they divert the host cell's metabolism into synthesizing viral building blocks, which then self-assemble into new virus particles that are released into the environment. During the process of this synthesis, viruses utilize cellular metabolic energy, many cellular enzymes, and cellular organelles that they are unable to produce. For this reason, they are incapable of sustaining an independent synthesis of their own components. The extracellular virus particle is called a virion (Fig. 1), whereas the name virus is reserved for various phases of the intracellular development. In addition, animal viruses are not susceptible to the action of antibiotics. See also: Antibiotic; Cell (biology); Deoxyribonucleic acid (DNA); Nucleic acid; Ribonucleic acid (RNA); Virus; Virus classification
Virions are small, 20–300 nm in diameter, and pass through filters that retain most bacteria. However, large virions (for example, vaccinia, which is 300 nm in diameter) exceed the size of some smaller bacteria. The major structural components of the virion are proteins and nucleic acid, but some virions also possess a lipid-containing membranous envelope. The protein molecules are arranged in a symmetrical shell, called the capsid, around the DNA or RNA. The shell and the nucleic acid constitute the nucleocapsid. See also: Protein
In electron micrographs of low resolution, virions appear to possess two basic shapes: spherical and cylindrical. High-resolution electron microscopy and x-ray diffraction studies of crystallized virions reveal that the "spherical" viruses are in fact polyhedral in their morphology, whereas the "cylindrical" virions display helical symmetry. The polyhedron most commonly encountered in virion structures is the icosahedron, in which the protein molecules are arranged on the surface of 20 equilateral triangles. Based on these morphological features, viruses are classified as helical or icosahedral (Fig. 1). Certain groups of viruses do not exhibit any discernible features of symmetry and are classified as complex virions. Further distinction is made between virions containing RNA or DNA and between those with naked or enveloped nucleocapsids.
Viral nucleic acid
The outer protein shell of the virion furnishes protection to the most important component, that is, the viral genome, shielding it from destructive enzymes (ribonucleases or deoxyribonucleases). The viral genome carries information that specifies all viral structural and functional components required for the initiation and establishment of the infectious cycle and for the generation of new virions. This information is expressed in the alphabet of the genetic code (the sequence of nucleotides) and may be contained in a double-stranded or single-stranded DNA, or double-stranded or single-stranded RNA. The viral DNA may be linear or circular, and the viral RNA may be a single long chain or a number of shorter chains (fragmented genomes), with each containing different genetic information. Furthermore, some RNA viruses have the genetic information expressed as a complementary nucleotide sequence. These are classified as negative-strand RNA viruses. Finally, RNA tumor viruses have an intracellular DNA phase, during which the genetic information contained in the virion RNA is transcribed into DNA and integrated into the host cell's genome. The discovery of this process came as a surprise to scientists because it was believed that the flow of genetic information was unidirectional from DNA to RNA to protein and could not take place in the opposite direction, that is, from RNA to DNA. The transcription of RNA to DNA was termed reverse transcription, and RNA tumor viruses are sometimes referred to as retroviruses. See also: Genetic code; Reverse transcriptase; Tumor viruses
When introduced into a susceptible cell by either chemical or mechanical means, the naked viral nucleic acid is itself infectious in most cases. Two exceptions are negative-strand RNA viruses and RNA tumor viruses. In these cases, RNA has to be first transcribed and reverse-transcribed, respectively, into the proper form of genetic information before the infectious process can take place. This task is carried out by means of an enzyme that is contained in the protein shell of the virion nucleocapsid. The whole nucleocapsid is therefore required for infectivity. See also: Infection; Infectious disease
Viral infection is composed of several steps: adsorption, penetration, uncoating and eclipse, and maturation and release.
Adsorption takes place on specific receptors in the membrane of an animal cell. The presence or absence of these receptors determines the tissue or species susceptibility to infection by a virus. Enveloped viruses exhibit surface spikes that are involved in adsorption; however, most animal viruses do not possess obvious attachment structures.
Penetration takes place through invagination and ingestion of the virion by the cell membrane (phagocytosis or viropexis). In addition, enveloped viruses often enter the cell by a process of fusion of the virion and cell membranes. Penetration is followed by uncoating of the nucleic acid or (in some cases) by uncoating of the nucleocapsid. At this stage, the identity of the virion has disappeared, and viral infectivity cannot be recovered from disrupted cells. See also: Cell membrane; Phagocytosis
The absence of infectious particles in cell extracts is characteristic of the eclipse period. During eclipse, the biochemical processes of the cell are manipulated to synthesize viral proteins and nucleic acids. The survival of viruses depends on this subversive ability. In the process of evolution, viruses have developed an extraordinary efficiency and a remarkable repertoire of strategies. The eclipse period in infections with DNA viruses starts with the transcription of the genetic information in the nucleus of the cell (poxviruses are exceptions), processing into messenger RNAs (mRNAs), and translation into proteins (in the cytoplasm). This process is divided into early and late transcription. In the absence of newly synthesized viral components, the immediate early events must be entirely catalyzed by cellular enzymes. However, the early proteins are virus-encoded functional proteins that will participate in the synthesis of viral DNA and of intermediate and late viral proteins, as well as in the shutoff of various cellular functions that might be detrimental to viral synthesis. The event that distinguishes early from late mRNA transcription and translation is the onset of viral DNA synthesis. The major late products are the structural proteins of the nucleocapsid. Almost as soon as these proteins are synthesized, they assemble with newly synthesized DNA molecules into virion nucleocapsids. The appearance of these particles signals the end of the eclipse period. See also: Transcription
The events of the eclipse period in infections with RNA viruses are similar, except that they take place in the cytoplasm (influenza viruses are exceptions), and a division into early and late transcription cannot be made. In the case of positive-strand RNA viruses, the viral RNA is itself the mRNA. In infections with negative-strand RNA viruses, the virion RNA in the nucleocapsid is first transcribed into positive mRNAs. Intracellular nucleocapsids are present throughout the entire infectious cycle, and the eclipse period cannot be defined in the classical sense. RNA tumor viruses reverse-transcribe their RNA into DNA, which enters the cell nucleus and becomes integrated into the cellular DNA. All viral mRNAs and genomic RNAs are generated by transcription of the integrated DNA.
Maturation and release
The event characteristic of the maturation step is virion assembly and release. In many cases, the protein shell is assembled first (procapsid) and the nucleic acid is inserted into it. During this insertion, processing of some shell proteins by cleavage takes place and is accompanied by a modification of the structure to accommodate the nucleic acid. Unenveloped viruses that mature in the cytoplasm (for example, poliovirus) often exit the cell rapidly by a reverse-phagocytosis process, even before the breakdown of the cell. In some cases, however, a large number of virus particles may accumulate inside the cell in crystalline arrays called inclusion bodies (Fig. 2). Viruses that mature in the nucleus are usually released slowly, and the damage to the cell is extensive. Enveloped viruses exit the cell by a process of budding. Viral envelope proteins (glycoproteins) become inserted at various sites into the cell membrane, where they also interact with matrix proteins and with nucleocapsids. The cellular membrane then curves around the complex and forms a bud that detaches from the rest of the cell.
Effect of viral infections
Two extreme types of effects are identified: lytic infections, which cause cell death by a variety of mechanisms, with cell lysis as the most common outcome; and persistent infections, accompanied either by no apparent change in the host cell or by some interference with normal growth control, as in transformation of normal to cancer cells. The degenerative phenomena in tissue cultures during a lytic infection are called cytopathic or cytolytic effects. In animals, extensive destruction of tissue may accompany an infection by a lytic virus. See also: Lytic infection
As a defense to certain conditions of infection, animal cells generate substances called interferons that, by a complex mechanism, inhibit replication of viruses. They are specific to the cell species from which they were derived, but not to the virus that elicited their generation. For example, mouse interferon will protect mouse cells, but not human cells, from any viral infection.
Virus infections spread in several ways: through aerosols and dust, by direct contact with carriers or their excretions, and by bites or stings of animal and insect vectors. At the point of entry, infected cells undergo viremia, appearing in the blood. From there, the virus becomes disseminated by secretions. It is carried through the lymphatic system and bloodstream to other target organs, where secondary viremias occur (except in localized infections, such as warts). In most cases, viral infections are of short duration and great severity. However, persistent infections are not uncommon. See also: Virus infection, latent, persistent, slow
The afflicted organism mounts a variety of defenses, and the most important defense is the immune response. Circulating antibodies against viral proteins are generated. Those antibodies interacting with virion surface proteins neutralize the infectious potential of the virus. Although the antibodies are specific against the virus that has elicited them, they will cross-react with closely related virus strains. The specificity of neutralizing antibodies obtained from experimentally injected animals is utilized for diagnostic purposes or in quantitative assays. In addition to the circulating antibodies, cell-mediated immune responses also take place. The most important of these is the production of cytotoxic thymus-derived lymphocytes, found in the lymph nodes, spleen, and blood. They destroy all cells that harbor viral glycoproteins in their membranes, regardless of whether these cells are actively involved in virus synthesis or acquired the viral proteins by membrane fusion with inactive virions or cell debris. The cell-mediated immunity has been demonstrated to be more important to the process of recovery than circulating antibodies. In spite of their beneficial role, immune responses often seriously contribute to the pathology of the disease. Circulating antigen–antibody complexes can lodge in organs and cause inflammation. Moreover, cell-mediated responses have been known to produce severe shock syndromes in patients with a history of previous exposures to the virus. See also: Antibody; Antigen; Antigen-antibody reaction; Autoimmunity; Cellular immunology; Immunity; Virus interference
Viruses are resistant to the antibiotics commonly used against bacterial infections. The use of chemotherapeutic agents with antiviral activity is plagued by their toxicity to the animal host. However, the application of vaccines has been successful in the control of many viruses. Vaccines elicit immune responses and often provide lifelong protection. Two types of vaccines have been applied: inactivated virus and live attenuated virus. Various inactivation procedures are available. See also: Chemotherapy and other antineoplastic drug treatments; Vaccination; Virus chemoprophylaxis
In order to achieve full protection, it is important that the vaccine contain all the distinct antigenic types of the virus. Development of monoclonal antibodies [antibody proteins that bind to a specific target molecule (antigen) at one specific site (antigenic site)] has led to a better characterization of these types in naturally occurring viruses. This information is subsequently used to develop better vaccines. See also: Monoclonal antibodies