In research, viruses have provided both tools and model systems for our discovery of the fundamental principles of molecular biology. The first genes mapped, the first regulatory switches defined, and the first genomes to be sequenced were all those of viruses. Vectors for gene cloning and gene therapy today continue to be derived from viruses.fresh news ON VIRUS and our function In this chapter, we introduce major themes of virus structure and function and the fundamental challenges that all viruses face: genome packaging, cell attachment and entry, and the molecular strategies that enable viruses to divert the metabolism of their host cell. Viruses provide key tools and model systems for molecular biology. Our understanding of viruses, particularly bacterial viruses, called bacterio phages, provides a useful back-ground for the molecular biology we will encounter in Part 2 of this articles. The molecular biology of viral life cycles is explored further in Chapter 11, and viral disease pathology and epidemiology are discussed in Chapters 25-27.
what is a virus?
A virus is a noncellular particle capable of infecting a ho cell, where it reproduces. The virus particle, or virito consists of an infective nucleic acid (DNA or RNA) contained within a protective shell made of protein, called the capsid. The capsid usually has a molecular delivery device that enables transfer of the virion's genome into the host cell. Viruses that infect bacteria are known as bacteriophages or phages. An example is bacteriophage T2, which infects Escherichia coil . The T2 and 14 phages have a capsid with a tail that inserts the viral genome into the host cell, where it directs reproduction of progeny virions. Virions are released when the host cell lyses. As cells lyse, their disappearance can be observed as a plaque, a clear spot against a lawn of bacterial cells . Each plaque arises from a single irion or phage particle that lyses a host cell and spreads geny to infect adjacent cells. Plaques can be counted representing individual infective virions from a phage spension. An example of a virus that infects humans is measles s. The measles virion has an envelope of membrane ' t, during infection, fuses with the host cell membrane. r replicating within the infected cell, newly formed asles capsids become enveloped by host cell membrane they bud out of the host cell . The spreading s generates a rash of red spots on the skin of infected dents and is occasionally fatal (one in 500 Plants are also infected by viruses, such as tobacco ic virus (TMV) Within the plant cell, virions acculate to high numbers and trawl through [connections to neighboring cells. Infection by tobacco ic virus results in mottled leaves and stunted growth Plant viruses cause major economic losses in ulture worldwide.Each species of virus infects a particular group of host species, known as the host range. Some viruses can infect only a single species; for example, HIV infects only humans. Close relatives of humans, such as the chimpanzee, are not infected, although they are SUKeptible to a closely related virus, simian immunode cy virus (Sly). On the other hand, the West us, transmitted by mosquitoes, has a much b er host range, including many species of birds and mammals.
Viruses Propagate Their Genomic Information
Viral propagation exemplifies the central role of information in biological reproduction. The propagation of viruses is mimicked by the spread of "computer viruses," whose information "infects" computer memory. When a biological virus infects a host cell, the information in its genome subverts the host cell machinery to produce multiple copies of the virus; the multiple copies then escape to infect more host cells. Similarly, when a computer virus infects a host computer, its program code subverts the host to produce multiple copies of the virus, which then escape to infect more host computers. Computer viruses generate epidemics analogous to those of biological viruses. The virus's code can even be designed to "mutate" in order to foil the "immune system" of antivirus software.Viruses Infect All Forms of Life
'Viruses are ubiquitous, infecting every taxonomic group of organisms, including bacteria, eukaryotes, and archaea. In marine ecosystems, viruses act as major predators and sequester significant amounts of nutrients. For humans, viruses cause many forms of illness, whose influence on our history and culture would be hard to over-state. More people died of influenza in the global epidemic of 1918 than in the battles of World War In the past 30 years, the AIDS pandemic caused by HIV has killed 25 million people worldwide and continues to grow. Viruses are part of our daily lives. The most frequent infections of college students are due to respiratory pathogens such as rhinovirus (the common cold) and Epstein-Barr virus (infectious mononucleosis), as well as sexually transmitted viruses such as herpes simplex (HSV) and papilloma (genital warts). Viruses also impact human industry; for example, bacteriophages (literally, "bacteria-eaters") infect cultures of Lactococcus during the production of yogurt and cheese. Plant pathogens such as cauliflower mosaic virus and rice dwarf virus continue to cause substantial losses in agriculture. In contrast to our vast arsenal of antibiotics (effective against bacteria), the number of antiviral drugs remains depressingly small. Because the machinery of viral growth is largely that of the host cell, viruses present relatively few targets that can be attacked by antiviral drugs with out harming the host. However, a understanding of viral life cycles a the molecular level is now leadi to the development of new anti rat drugs, such as AZT and prote inhibitors, which combat HIV.Despite their lethal potentil viruses have made surprising cont butions to medical research. Ateriophage provides a protein that lyses the cell walls 0 anthrax bacteria. Other bacteriophages are used as cloic ing vectors, small genomes into which foreign genes car be inserted and cloned for gene technology. Even leth viruses such as HIV are being developed as vectorsfol human gene therapy. Some viruses introduce copies of their own genom into the host's genome, a process that can mediate ev lution of the host genome. Indeed, studies of molec evolution reveal that viral genomes are the antes source of about a tenth of the human genome.
Viral Genomes
The genome of a virus can be small, encoding fewer ten genes. In cauliflower mosaic virus, for examhipl genome encodes only seven genes , wch ally overlap each other in sequence. This overlap in is made possible by the use of different reading start positions for translating codons to amino acids. viral genomes, such as that of avian leukosis genom encoded by RNA. The RNA genome of avian leukos has protein-encoding genes grouped by functio egories of core capsid, replicative enzymes, and e proteins. On the other hand, larger viral genomes, such: of herpes virus or of bacteriophage T4, have gen, persed around the chromosome, similar to the gen bacteria. The giant Mimi virus, which infects ame may cause human pneumonia, is as large as some
Infective Genomes with No Capsid
Early in the twentieth century, viruses were believed to be the smallest particles capable of infecting hosts and propagating themselves. Then even smaller virus like infectiou, agents were discovered for which the nucleic acid genuine is itself the entire infectious particle; there is no protective capsid. Such infectious agents are called viroids. \4ost viroids are RNA molecules that infect plants. An example is the potato spindle tuber viroid. This viroid consists of a circular, single-stranded molecule of RNA that doubles back on itself to form base pairs interrupted by s ort unpaired loops. The RNA folds globular structure that interacts with host
cell proteins. Most critically, the RNA genome requires a host RNA-dependent RNA polymerase to replicate itself and transcribe its genes. RNA dependent RNA polymerases occur normally in plant cells, where they contribute to regulation of gene expression. During viroid infection, the RNA-dependent RNA polymerase replicates progeny copies of the viroid, which encodes no products other than itself. Viroids can cause as much host destruction as "true viruses," and some authors, particularly in plant pathology, classify them as "viruses without capsids." Some viroids have catalytic ability, comparable to enzymes made of protein. An RNA molecule capable of catalyzing a reaction is called a ribozyme. One class of plant-infecting viroids are the hammerhead ribozymes. Named for their hammer-shaped tertiary structure, hammerhead ribozymes possess the ability to cleave themselves or other specific RNA molecules. Their ability to cleave very specific RNA sequences has applications in medical research. Hammerhead ribozymes have been engineered to cleave human RNA molecules involved in cancer or in infection by viruses such as HIV. The engineering of ribozymes for medical therapy is an exciting field of biotechnology.
Infection with Out Nucleic Acid?
A remarkable class of infectious agents is believed to consist of protein only. These agents, known as prions, are believed to be aberrant proteins arising from the host cell. Prions gained notoriety when they were implicated in brain infections such as Creutzfeldt-Jakob disease, popularly known as "mad cow" disease because it mayVirus Structure
A packaged structure of a virus achieves two goals: It keeps the viral genome intact, and it enables infection of the appropriate host cell. First, the stable capsid protects the viral genome from degradation and enables it to be transmitted outside the host. Second, in order for the viral genome to reproduce, the virion must either insert its genome into the host cell or disassemble within the host. In the process, the original particle loses its stable structure and its own identity as such, but it generates numerous progeny virions.Symmetrical virus Particles
Different viral species make different forms of capsids. Virus particles may be symmetrical, in which case the capsid is one of two types, icosahedral or filamentous. Each type of capsid exhibits geometrical symry. The advantage of symmetry is that it provides a to form a package out of repeating protein units gen-by a small number of genes and encoded by a short osomal sequence. The smaller the viral genome, ore genome copies can be synthesized from the host limited supply of nucleotides. Nevertheless, other s, such as smallpox virus, are asymmetrical and ave much larger genomes. Large genomes offer a r range of functions for viral components. leosahedrai viruses. Many viruses package their genome in an icosahedral (20-sided) capsid; examples include poliovirus and the herpes viruses. Icosahedral viral capsids take the form of a polyhedron with 20 identical triangu-lar faces. Bacteriophages often supplement the icosahedral capsid or head coat with an elaborate delivery device. For example, bacteriophage T4 has a complex struc-ture consisting of an icosahedral headpiece containing the genome, six jointed "legs" that stabilize the structure on the host cell surface, and a neck piece that channels the nucleic acid into the host cell. The structure of phage T4 was first observed by microbiologists during the rise of the NASA space program, and its form was compared to that of the "lunar module" that landed on the moon. Indeed, in the 1960s, the "tailed phages," such as phage T4 and phage lambda, were to molecular biology what the lunar landings were to space exploration.In the capsid, each triangle can be composed of three identical but asymmetrical protein units. An example of an icosahedral capsid is that of the herpes simplex virus. Each triangular face of the capsid is determined by the same genes encoding the same protein subunits. No matter what the pattern of subunits in the triangle, the structure overall exhibits rotational symmetry characteristic of an icosahedron: threefold symmetry around the axis through two opposed triangular faces; five-fold symmetry around an axis through opposite points; and twofold symmetry around an axis through opposite edges. Capsid symmetry is important for structure determination and visualization and for the design of antiviral drugs. Virus particles can be observed by standard transmis-sion electron microscopy (TEM), but the details of capsid structure as in Figure A require visualization by digital reconstruction of cryo EM (discussed in Section). Recall from Chapter 2 that in cryo EM, the viral samples for TEM are prepared flash-frozen, preventing formation of ice crystals. Flash freezing enables observation without stain. The electron beams penetrate the object; thus, images of individual capsids actually provide a glimpse of the virus's internal contents. By digitally combining and processing cryo TEM images from a number of capsids, a three-dimensional reconstruction is built for the entire virus particle. In some icosahedral viruses, the capsid is enclosed in an envelope composed of membrane from the host cell in which the virion formed. Figure A shows how herpes virions capture cell membrane to form their envelopes as
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