chapter 19 from textbook

Key Concepts

19.1: A virus consists of nucleic acid surrounded by a protein coat.
19.2: Viruses replicate only in host cells.
19.3: Viruses and prions are formidable pathogens in animals and plants.

Superset 19: A Borrowed Life

Viruses hijack cells by injecting genetic information, using cellular machinery to create new viruses and spread infection.
HIV destroys immune system cells, leading to AIDS if untreated.
Viruses are smaller and simpler than eukaryotic and prokaryotic cells.
Viruses lack cellular structures and metabolic machinery; they consist of genes in a protein coat.
Viruses exist in a gray area between life and non-life, leading a "borrowed life."

Viruses and Molecular Biology

Molecular biology originated from studying viruses that infect bacteria.
Experiments with viruses showed that genes are nucleic acids and helped understand DNA replication, transcription, and translation.

Chapter 19 Overview

Covers virus structure, replication, role as pathogens, and prions.

Concept 19.1: Virus Structure

Viruses were detected indirectly before being seen.

Discovery of Viruses: Scientific Inquiry

Tobacco mosaic disease stunts tobacco plant growth.
In 1883, Adolf Mayer transmitted the disease by rubbing sap from diseased plants onto healthy ones.
- Mayer thought tiny, invisible bacteria caused the disease.
Dmitri Ivanowsky filtered sap from infected leaves to remove bacteria, but the filtered sap still caused mosaic disease.
- Ivanowsky suggested bacteria were either small enough to pass through filters or produced a toxin that could.
Martinus Beijerinck showed the infectious agent in filtered sap could replicate within the host.
- The agent couldn't be cultivated on nutrient media like bacteria.
- Beijerinck proposed a replicating particle smaller and simpler than a bacterium, coining the concept of a virus.
In 1935, Wendell Stanley crystallized tobacco mosaic virus (TMV).
Later, electron microscopes allowed the visualization of TMV and other viruses.

Figure 19.2: Inquiry - What causes tobacco mosaic disease?

Sap extracted from diseased tobacco plants.
Sap passed through a bacteria-trapping porcelain filter.
Filtered sap rubbed on healthy tobacco plants.
Healthy plants became infected.

Results: Filtered sap infected healthy plants, and their sap could infect more plants.
Conclusion: The infectious agent wasn't a bacterium because it passed through the filter and replicated in plants.
Note: The ability to cause disease remained undiluted after several transfers from plant to plant indicating pathogen replication.

WHAT IF? If the infection weakened with each group and eventually stopped, Beijerinck might have concluded the agent wasn't replicating.

Structure of Viruses

The tiniest viruses are 20 nm in diameter, smaller than a ribosome.
The largest virus is 1,500 nm (1.5 µm) in diameter and barely visible under a light microscope.
Stanley's crystallization of viruses was puzzling because even the simplest cells can't form crystals.
Viruses are infectious particles with nucleic acid enclosed in a protein coat, sometimes with a membranous envelope.

Viral Genomes

Viral genomes can be double-stranded DNA, single-stranded DNA, double-stranded RNA, or single-stranded RNA.
Viruses are called DNA viruses or RNA viruses based on their nucleic acid.
Genomes are usually single, linear, or circular molecules, but some viruses have multiple molecules.
The smallest viruses have three genes; the largest have hundreds to 2,000.
Bacterial genomes have 200 to a few thousand genes.

Capsids and Envelopes

The capsid is the protein shell enclosing the viral genome.
Capsids can be rod-shaped, polyhedral, or complex.
They are made of protein subunits called capsomeres; the number of protein types in a capsid is usually small.
Tobacco mosaic virus has a rigid, rod-shaped capsid made from over 1,000 molecules of a single protein type in a helix, called helical viruses (Figure 19.3a).
Adenoviruses, which infect animal respiratory tracts, have 252 identical protein molecules in a polyhedral capsid with 20 triangular facets (icosahedron), called icosahedral viruses (Figure 19.3b).
Some viruses have accessory structures for infecting hosts.
Membranous envelopes surround the capsids of influenza viruses and other animal viruses (Figure 19.3c).
Viral envelopes come from host cell membranes, containing host cell phospholipids and membrane proteins, as well as viral proteins and glycoproteins.
Glycoproteins are proteins with covalently attached carbohydrates.
Some viruses carry viral enzyme molecules within their capsids.
Bacteriophages, or phages, are viruses that infect bacteria and have complex capsids.
The first phages studied infected Escherichia coli and were named T1, T2, etc.
T-even phages (T2, T4, T6) are similar in structure, with elongated icosahedral heads enclosing DNA and protein tails with fibers for attaching to bacterial cells (Figure 19.3d).

Concept 19.2: Viral Replication in Host Cells

Viruses lack metabolic enzymes and ribosomes, making them obligate intracellular parasites that replicate only within a host cell.
Isolated viruses are packaged sets of genes in transit between host cells.
Each virus infects a limited number of host species, known as the host range, due to recognition systems.
Viruses identify host cells via a "lock-and-key" fit between viral surface proteins and cell receptor molecules.
- Receptor molecules originally benefited the host cell but were co-opted by viruses.
Some viruses, like West Nile and equine encephalitis, infect mosquitoes, birds, horses, and humans.
Others, like measles, infect only humans.
Viral infection in multicellular eukaryotes is tissue-specific (e.g., cold viruses infect upper respiratory tract cells, HIV binds to immune cells).

General Features of Viral Replicative Cycles

Viral infection starts with virus binding to a host cell and the viral genome entering.
Genome entry mechanism depends on the virus and host cell type.
T-even phages use tail fibers to inject DNA into bacteria.
Other viruses enter by endocytosis or, in enveloped viruses, by fusion with the host's plasma membrane.
Once inside, viral proteins commandeer the host to copy the viral genome and produce viral proteins.
The host provides nucleotides, enzymes, ribosomes, tRNAs, amino acids, ATP, and other components.
DNA viruses use host cell DNA polymerases for genome synthesis.
RNA viruses use virally encoded RNA polymerases that use RNA as a template (uninfected cells lack these enzymes).

Viral Nucleic Acid Assembly

Viral nucleic acid molecules and capsomeres self-assemble into new viruses.
TMV RNA and capsomeres can be mixed to reassemble complete viruses.
The simplest viral replicative cycle ends with hundreds or thousands of viruses exiting the host cell, often damaging or destrorying it.
Such cellular damage and death, along with the body’s responses, cause viral infection symptoms.
Progeny viruses can infect additional cells, spreading the infection.
There are many variations on this basic cycle in phages and animal viruses; plant viruses are considered later.

Replicative Cycles of Phages

Phages are the best-understood viruses, and some are complex.
Research on phages showed that some double-stranded DNA viruses replicate via the lytic and lysogenic cycles.

Lytic Cycle

A phage replicative cycle that kills the host cell is called a lytic cycle.
- The bacterium lyses (breaks open) and releases produced phages.
successive lytic cycles can destroy a bacterial population in hours.
A phage that replicates only by a lytic cycle is a virulent phage.

Lysogenic Cycle

Many phages coexist with host cells in lysogeny.
The lysogenic cycle allows phage genome replication without destroying the host.
Phages capable of both modes are temperate phages.
Phage l is a temperate phage used in biological research.
- It infects E. coli cells by binding to the surface and injecting its linear DNA genome.

After the viral nucleic acid molecules and capsomeres are produced, they spontaneously self-assemble into new viruses. In fact, researchers can separate the RNA and capsomeres of TMV and then reassemble complete viruses simply by mixing the components together under the right conditions. The simplest type of viral replicative cycle ends with the exit of hundreds or thousands of viruses from the infected host cell, a process that often damages or destroys the cell. Such cellular damage and death, as well as the body’s responses to this destruction, cause many of the symptoms associated with viral infections. The viral progeny that exit a cell have the potential to infect additional cells, spreading the viral infection. There are many variations on the simplified viral replicative cycle we have just described. We will now take a look at some of these variations in bacterial viruses (phages) and animal viruses; later in the chapter, we will consider plant viruses.
Release. The phage directs production of an enzyme that damages the bacterial cell wall, allowing fluid to enter. The cell swells and finally bursts, releasing 100 to 200 phage particles. 5Attachment. The T4 phage uses its tail fibers to bind to specific surface proteins on an E. coli cell that act as receptors. 1Entry of phage DNA and degradation of host DNA. The sheath of the tail contracts, injecting the phage DNA into the cell and leaving an empty capsid outside. The cell’s DNA is hydrolyzed. 2 Synthesis of viral genomes and proteins. The phage DNA directs production of phage proteins and copies of the phage genome by host and viral enzymes, using components within the cell. Self-assembly. Three separate sets of 3 proteins self-assemble to form phage heads, tails, and tail fibers. The phage genome is packaged inside the capsid as the head forms. 4

Figure 19.5 The lytic cycle of phage T4, a virulent phage.
Phage T4 has almost 300 genes, which are transcribed and translated using the host cell’s machinery. One of the first phage genes translated after the viral DNA enters the host cell codes for an enzyme that degrades the host cell’s DNA (step 2 ); the phage DNA is protected from breakdown because it contains a modified form of cytosine that is not recognized by the phage enzyme. The entire lytic cycle, from the phage’s first contact with the cell surface to cell lysis, takes only 20–30 minutes at 37°C.
Animation: Phage Lytic Cycle

Lambda Phage Infection

Infection of an E. coli cell by phage λ begins when the phage binds to the surface of the cell and injects its linear DNA genome (Figure 19.6). Within the host, the λ DNA molecule forms a circle. What happens next depends on the replicative mode: lytic cycle or lysogenic cycle. During a lytic cycle, the viral genes immediately turn the host cell into a λ-producing factory, and the cell soon lyses and releases its virus progeny. During a lysogenic cycle, however, the λ DNA molecule is incorporated into a specific site on the E. coli chromosome by viral proteins that break both circular DNA molecules and join them to each other. When integrated into the bacterial chromosome in this way, the viral DNA is known as a prophage.
One prophage gene codes for a protein that prevents transcription of most of the other prophage genes. Thus, the phage genome is mostly silent within the bacterium. Every time the E. coli cell prepares to divide, it replicates the phage DNA along with its own chromosome such that each daughter cell inherits a prophage. A single infected cell can quickly give rise to a large population of bacteria carrying the virus in prophage form. This mechanism enables viruses to propagate without killing the host cells on which they depend.

The term lysogenic signifies that prophages are capable of generating active phages that lyse their host cells. This occurs when the λ genome (or that of another temperate phage) is induced to exit the bacterial chromosome and initiate a lytic cycle. An environmental signal, such as a certain chemical or high-energy radiation, usually triggers the switchover from the lysogenic to the lytic mode.

In addition to the gene for the viral protein that prevents transcription, a few other prophage genes may be expressed during lysogeny. Expression of these genes may alter the host’s phenotype, a phenomenon that can have important medical significance. For example, the three species of bacteria that cause the human diseases diphtheria, botulism, and scarlet fever would not be so harmful to humans without certain prophage genes that cause the host bacteria to make toxins. And the difference between the E. coli strain in our intestines and the O157:H7 strain that has caused several deaths by food poisoning appears to be the presence of toxin genes of prophages in the O157:H7 strain.

Bacterial Defenses Against Phages

After reading about the lytic cycle, you may have wondered why phages haven’t exterminated all bacteria. Lysogeny is one major reason why bacteria have been spared from extinction caused by phages. Bacteria also have their own defenses against phages.
First, natural selection favors bacterial mutants with surface proteins that are no longer recognized as receptors by a particular type of phage.
Second, when phage DNA does enter a bacterium, the DNA often is identified as foreign and cut up by cellular enzymes called restriction enzymes, which are so named because they restrict a phage’s ability to replicate within the bacterium. (Restriction enzymes are used in molecular biology and DNA cloning techniques; see Concept 20.1.) The bacterium’s own DNA is methylated in a way that prevents attack by its own restriction enzymes.
A third defense is a system present in both bacteria and archaea called the CRISPR-Cas system.
The CRISPR-Cas system was discovered during a study of repetitive DNA sequences present in the genomes of many prokaryotes. These sequences, which puzzled scientists, were named clustered regularly interspaced short palindromic repeats (CRISPRs) because each sequence read the same forward and backward (a palindrome), with different stretches of “spacer DNA” in between the repeats. At first, scientists assumed the spacer DNA sequences were random and meaningless, but analysis by several research groups showed that each spacer sequence corresponded to DNA from a particular phage that had infected the cell.
Further studies revealed that particular nuclease proteins interact with the CRISPR region. These nucleases, called Cas (CRISPR-associated) proteins, can identify and cut phage DNA, thereby defending the bacterium against phage infection. When a phage infects a bacterial cell that has the CRISPR-Cas system, the DNA of the invading phage is integrated into the genome between two repeat sequences. If the cell survives the infection, any further attempt by the same type of phage to infect this cell (or its offspring) triggers transcription of the CRISPR region into RNA molecules (Figure 19.7). These RNAs are cut into pieces and then bound by Cas proteins. The Cas protein uses a portion of the phage-related RNA as a homing device to identify the invading phage DNA and cut it, leading to its destruction. In Concept 20.1, you’ll learn how this system is used in the laboratory to alter genes in other cells.
Just as natural selection favors bacteria that have receptors altered by mutation or that have enzymes that cut phage DNA, it also favors phage mutants that can bind to altered receptors or that are resistant to enzymes. Thus, the bacterium-phage relationship is in constant evolutionary flux.

Replicative Cycles of Animal Viruses

Everyone has suffered from viral infections, whether cold sores, influenza, or the common cold. Like all viruses, those that cause illness in humans and other animals can replicate only inside host cells. Many variations on the basic scheme of viral infection and replication are represented among the animal viruses. One key variable is the nature of the viral genome (double- or single-stranded DNA or RNA). Another variable is the presence or absence of a membranous envelope. Whereas few bacteriophages have an envelope or RNA genome, many animal viruses have both. In fact, nearly all animal viruses with RNA genomes have an envelope, as do some with DNA genomes.
Rather than consider all the mechanisms of viral infection and replication, we will focus first on the roles of viral envelopes and then on the functioning of RNA as the genetic material of many animal viruses.

Viral Envelopes

An animal virus equipped with an envelope—that is, a membranous outer layer—uses it to enter the host cell.
Protruding from the outer surface of this envelope are viral glycoproteins that bind to specific receptor molecules on the surface of a host cell. Figure 19.8 outlines the events in the replicative cycle of an enveloped virus with an RNA genome. Ribosomes bound to the endoplasmic reticulum (ER) of the host cell make the protein parts of the envelope glycoproteins; cellular enzymes in the ER and Golgi apparatus then add the sugars. The resulting viral glycoproteins, embedded in membrane derived from the host cell, are transported to the cell surface. In a process much like exocytosis, new viral capsids are wrapped in membrane as they bud from the cell. In other words, the viral envelope is usually derived from the host cell’s plasma membrane, although all or most of the molecules of this membrane are specified by viral genes. The enveloped viruses are now free to infect other cells. This replicative cycle does not necessarily kill the host cell, in contrast to the lytic cycles of phages.
Some viruses have envelopes that are not derived from plasma membrane. Herpesviruses, for example, are temporarily cloaked in membrane derived from the nuclear envelope of the host; they then shed this membrane in the cytoplasm and acquire a new envelope made from membrane of the Golgi apparatus. These viruses have a double-stranded DNA genome and replicate within the host cell nucleus, using a combination of viral and cellular enzymes to replicate and transcribe their DNA. In the case of herpesviruses, copies of the viral DNA can remain behind as mini-chromosomes in the nuclei of certain nerve cells. There they remain latent until some sort of physical or emotional stress triggers a new round of active virus production. The infection of other cells by these new viruses causes the blisters characteristic of herpes, such as cold sores or genital sores. Once someone acquires a herpesvirus infection, flare-ups may recur throughout the person’s life.

Viral Genetic Material

. All viruses that use an RNA genome as a template for mRNA transcription require RNA → RNA synthesis. These viruses use a viral enzyme capable of carrying out this process; there are no such enzymes in most cells. The enzyme used in this process is encoded by the viral genome, and after its synthesis the protein is packaged during viral self-assembly with the genome inside the viral capsid.
The RNA animal viruses with the most complicated replicative cycles are the retroviruses (class VI). These viruses have an enzyme called reverse transcriptase that transcribes an RNA template into DNA, an RNA → DNA information flow that is the opposite of the usual direction. This unusual phenomenon is the source of the name retroviruses (retro means “backward”). Of particular medical importance is HIV (human immunodeficiency virus) that causes AIDS (acquired immunodeficiency syndrome). HIV and other retroviruses are enveloped viruses that contain two identical molecules of single-stranded RNA and two molecules of reverse transcriptase.
The HIV replicative cycle is typical of a retrovirus. After HIV enters a host cell, its reverse transcriptase molecules are released into the cytoplasm, where they catalyze synthesis of viral DNA. The newly made viral DNA then enters the cell’s nucleus and integrates into the DNA of a chromosome. The integrated viral DNA, called a provirus, never leaves the host’s genome, remaining a permanent resident of the cell. (Recall that a prophage, in contrast, leaves the host’s genome at the start of a lytic cycle.) The RNA polymerase of the host transcribes the proviral DNA into RNA molecules, which can function both as mRNA for the synthesis of viral proteins and as genomes for the new viruses that will be assembled and released from the cell.

Concept 19.3: Viruses and Prions as Formidable Pathogens

Diseases caused by viral infections afflict humans, agricultural crops, and livestock worldwide. Other smaller, less complex entities known as prions also cause disease in animals. We’ll first discuss animal viruses.

Viral Diseases in Animals

A viral infection can produce symptoms by a number of different routes. Viruses may damage or kill cells by causing the release of hydrolytic enzymes from lysosomes. Some viruses cause infected cells to produce toxins that lead to disease symptoms, and some have molecular components that are toxic, such as envelope proteins. How much damage a virus causes depends partly on the ability of the infected tissue to regenerate by cell division. People usually recover completely from colds because the epithelium of the respiratory tract, which the viruses infect, can efficiently repair itself. In contrast, damage inflicted by poliovirus to mature nerve cells is permanent because these cells do not divide and usually cannot be replaced. Many of the temporary symptoms associated with viral infections, such as fever and body aches, actually result from the body’s own efforts to defend itself against infection rather than from cell death caused by the virus.
The immune system is a critical part of the body’s natural defenses (see Chapter 43). It is also the basis for the major medical tool used to prevent viral infections—vaccines. A vaccine is a harmless derivative of a pathogen that stimulates the immune system to mount defenses against the harmful pathogen. Smallpox, a viral disease that was once a devastating scourge in many parts of the world, was eradicated by a vaccination program carried out by the World Health Organization (WHO). The very narrow host range of the smallpox virus—it infects only humans—was a critical factor in the success of this program. Similar worldwide vaccination campaigns are currently under way to eradicate polio and measles. Effective vaccines are also available to protect against rubella, mumps, hepatitis B, and a number of other viral diseases.
Although vaccines can prevent some viral illnesses, medical care can do little, at present, to cure most viral infections once they occur. The antibiotics that help us recover from bacterial infections are powerless against viruses. Antibiotics kill bacteria by inhibiting enzymes specific to bacteria but have no effect on eukaryotic or virally encoded enzymes. However, the few enzymes that are encoded only by viruses have provided targets for other drugs. Most antiviral drugs resemble nucleosides and thus interfere with viral nucleic acid synthesis.

Emerging Viruses

Viruses that suddenly become apparent are often referred to as emerging viruses. HIV, the AIDS virus, is a classic example: This virus appeared in San Francisco in the early 1980s, seemingly out of nowhere, although later studies uncovered a case in the Belgian Congo in 1959. A number of other dangerous emerging viruses cause encephalitis, inflammation of the brain. One example is the West Nile virus, which appeared in North America in 1999 and has spread to all 48 contiguous states in the United States, by now resulting in over 40,000 cases and almost 2,000 deaths.
How do such viruses burst on the human scene, giving rise to harmful diseases that were previously rare or even unknown?

Three processes contribute to the emergence of viral diseases.* The first, and perhaps most important, is the mutation of existing viruses. RNA viruses tend to have an unusually high rate of mutation because viral RNA polymerases do not proofread and correct errors in replicating their RNA genomes. Some mutations change existing viruses into new genetic varieties (strains) that can cause disease, even in individuals who are immune to the ancestral virus. For instance, seasonal flu epidemics are caused by new strains of influenza virus genetically different enough from earlier strains that people have little immunity to them. You’ll see an example of this process in the Scientific Skills Exercise, where you’ll analyze genetic changes in variants of the H1N1 flu virus and correlate them with spread of the disease. A second process that can lead to the emergence of viral diseases is the dissemination of a viral disease from a small, isolated human population. For instance, AIDS went unnamed and virtually unnoticed for decades before it began to spread around the world. In this case, technological and social factors, including affordable international travel, blood transfusions, sexual promiscuity, and the abuse of intravenous drugs, allowed a previously rare human disease to become a global scourge.

A third source of new viral diseases in humans is the spread of existing viruses from other animals. Scientists estimate that about three-quarters of new human diseases originate in this way. Animals that harbor and can transmit a particular virus but are generally unaffected by it are said to act as a natural reservoir for that virus. For example, the H1N1 virus that caused the 2009 flu pandemic mentioned earlier was likely passed to humans from pigs; for this reason, the disease it caused was originally called “swine flu.”

As we have seen, emerging viruses are generally not new; rather, they are existing viruses that mutate, disseminate more widely in the current host species, or spread to new host species. Changes in host behavior or environmental changes can increase the viral traffic responsible for emerging diseases. For instance, new roads built through remote areas can allow viruses to spread between previously isolated human populations. Also, the destruction of forests to expand cropland can bring humans into contact with other animals that may host viruses capable of infecting humans. Finally, genetic mutations and changes in host ranges can allow viruses to jump from one species to another.

Viral Diseases in Plants

Common signs of viral infection include bleached or brown spots on leaves and fruits stunted growth, and damaged flowers or roots, all of which can diminish the yield and quality of crops.
Plant viruses have the same basic structure and mode of replication as animal viruses. Most plant viruses discovered thus far, including tobacco mosaic virus (TMV), have a helical capsid, like TMV, while others have an icosahedral capsid (see Figure 19.3b).

Viral diseases of plants spread by two major routes.* In the first route, called horizontal transmission, a plant is infected from an external source of the virus. Because the invading virus must get past the plant’s outer protective layer of cells (the epidermis), a plant becomes more susceptible to viral infections if it has been damaged by wind, injury, or herbivores. Herbivores, especially insects, pose a double threat because they can also act as carriers of viruses, transmitting disease from plant to plant. Moreover, farmers and gardeners may transmit plant viruses inadvertently on pruning shears and other tools.
The other route of viral infection is vertical transmission, in which a plant inherits a viral infection from a parent. Vertical transmission can occur in asexual propagation (for example, through cuttings) or in sexual reproduction via infected seeds.

Once a virus enters a plant cell and begins replicating, viral genomes and associated proteins can spread throughout the plant by means of plasmodesmata, the cytoplasmic connections that penetrate the walls between adjacent plant cells. The passage of viral macromolecules from cell to cell is facilitated by virally encoded proteins that cause enlargement of plasmodesmata. Scientists have not yet devised cures for most viral plant diseases. Consequently, research efforts are focused largely on reducing the transmission of such