Family	Genus (or Subfamily)	Species or Typical Member	Infection/Disease
DNA Viruses
Parvoviridae	Erythrovirus	B19 virus	Erythema infectiosum
Papillomaviridae	Papillomavirus	Human papillomavirus (HPV)	More than 60 HPV types: common warts, plantar warts, flat cutaneous warts, etc.
Polyomaviridae	Polyomavirus	Polyomavirus	JC virus: Infection of the respiratory system, kidneys, or brain BK virus: Mild respiratory infection

Adenoviridae Mastadenovirus Human adenovirus 2 Gastrointestinal tract infections, infection of the conjunctiva, central nervous system infections, urinary tract infections Herpesviridae Alphaherpesvirinae

Herpes simplex virus 1 (HSV-1); human herpesvirus 1 (HHV-1)

Herpes simplex virus 2

(HSV-2); human herpesvirus 2 (HHV-2)

HSV-1: Oral and/or genital herpes (predominantly orofacial)

HSV-2: Oral and/or genital herpes (predominantly genital)

Varicellovirus Varicella-zoster virus (human herpesvirus 3 [HHV-3]) Chickenpox and shingles Gammaherpesvirinae

Epstein-Barr virus (EBV)

Lymphocryptovirus (HHV-4)

Kaposi’s sarcoma–associated herpesvirus (HHV-8)

HHV-4: Infectious mononucleosis, Burkitt’s lymphoma, CNS lymphoma in AIDS patients, posttransplant lymphoproliferative syndrome, nasopharyngeal carcinoma

HHV-8: Kaposi’s sarcoma, primary effusion lymphoma, some types of multicentric Castleman’s disease

Betaherpesvirinae Cytomegalovirus (HHV-5) Infectious mononucleosis, retinitis, etc. Roseolovirus Roseolovirus (HHV-6, -7) Sixth disease (roseola infantum or exanthema subitum) Poxviridae Orthopoxvirus

Smallpox (variola vera)

Vaccinia virus

Smallpox—eradicated

Vaccinia infections

Parapoxvirus Oral virus Cutaneous lesions Molluscipoxvirus Molluscum contagiosum virus Wartlike skin lesions Hepadnaviridae Orthohepadnavirus Hepatitis B virus Hepatitis B RNA Viruses Picornaviridae Enterovirus Poliovirus Poliomyelitis Rhinovirus Human rhinovirus A Common cold Hepatovirus Hepatitis A virus Hepatitis A Aphthovirus Foot-and-mouth disease virus Foot-and-mouth disease Caliciviridae Calicivirus Norovirus Gastroenteritis Astroviridae Astrovirus Human astroviruses (five serotypes) Gastroenteritis Togaviridae Alphavirus Sindbis virus Sindbis virus disease, polyarthritis and rash Ross River virus Epidemic polyarthritis Chikungunya virus Fever, petechial or maculopapular rash (limbs and trunk), arthralgia or arthritis Rubivirus Rubella virus Rubella Flaviviridae Flavivirus Yellow fever virus Yellow fever Dengue virus Dengue hemorrhagic fever Tick-borne encephalitis viurs Encephalitis Hepatitis C viruses Hepatitis C virus Hepatitis C Reoviridae Reovirus Reoviruses 1–3 Gastrointestinal and respiratory infections Rotavirus Human rotavirus A, B, and C Gastrointestinal infections Orbivirus Colorado tick fever virus Colorado tick fever (Mountain tick fever) Orthomyxoviridae Influenzavirus A, B Influenza A and B Influenza Influenza C Influenza C virus Influenza Paramyxoviridae Paramyxovirus Newcastle disease virus Zoonotic: Parainfluenza (influenza-like) Morbillivirus Measles virus (rubeola virus) Measles Rubulavirus Mumps virus Mumps Pneumovirus Respiratory syncytial virus Respiratory tract infections Rhabdoviridae Vesiculovirus Vesicular stomatitis virus Influenza-like symptoms; malaise, nausea, pain in limbs and back, possible vesicular lesions in mouth, lips and hands, leukopenia Lyssavirus Rabies virus Rabies Bunyaviridae Bunyavirus

Bunyamwera virus

La Crosse virus

Various arthropod-transmitted diseases Hantavirus Hantavirus, Puumala virus, Seoul virus Hemorrhagic fever with renal syndrome Nairovirus Crimean-Congo hemorrhagic fever virus Crimean-Congo hemorrhagic fever

Morphology

The size of viruses varies from very small, such as the parvovirus at about 20 nm and the poliovirus at 30 nm, to fairly large, such as the vaccinia virus at 400 nm and the poxviruses, which can be up to 450 nm. Most viruses cannot be visualized by light microscopy; therefore electron microscopy is used to examine their structure (see Chapter 1, Scope of Microbiology). However, some viruses are as large as or larger than the smallest bacteria and can be visualized by high optical magnification (Figure 7.1).

FIGURE 7.1 Size comparison between bacteria, viruses, viroids, and prions.

An exception to the size of other viruses is a virus discovered in 2003 by a team of French researchers, which named the organism mimivirus. This virus was found in free-living amoebas and has a diameter of 750 nm, which is larger than a Mycoplasma bacterium. These organisms also have the largest known viral genome, with about 1000 genes on a double-stranded circular DNA. Mimivirus seems to be an icosahedral particle with a diameter of 400 nm, no envelope, and surrounded by 80-nm fibrils.

Viruses consist of genetic material carried in a “shell” called the viral coat or capsid. The capsid consists of proteins that are coded by the viral genome. The capsid is a complex and highly organized entity that gives form to the virus and serves as the basis for morphological distinction. Subunits referred to as protomeres assemble to form capsomeres, which in turn spontaneously aggregate to form the capsid. Proteins associated with nucleic acids are called nucleoproteins and the association of viral capsid proteins with viral nucleic acid is referred to as a nucleocapsid. At the junction points of the capsomeres, long projections from the nucleocapsids, called spikes, are frequently attached (Figure 7.2). These spikes aid in attachment to the host cell membrane receptors. Some viruses have an envelope around the coat and once the virus is fully assembled it is called a virion. Depending on the presence or absence of an envelope, viruses are referred to as naked or enveloped viruses (Figure 7.3).

FIGURE 7.2 General structure of an animal virus.

FIGURE 7.3 Structure of A, a naked virus and B, an enveloped virus.

According to the shape and arrangement of capsomeres and the presence of an envelope, viruses can be classified into four distinct morphological types:

• Helical viruses

• Icosahedral viruses

• Enveloped viruses

• Complex viruses

Helical Viruses

Helical capsids have rod-shaped capsomeres, connected along their long axis, resembling a wide ribbon stacked around a central axis forming a helical structure with a central cavity, a hollow tube. As a result, these virions are rod shaped or filamentous and can be short and highly rigid, as in many plant viruses, or long and very flexible, as in many animal viruses. The genetic material can be single-stranded RNA (ssRNA) or single-stranded DNA (ssDNA) and is bound into the protein helix by the interactions between the negative charge on the nucleic acid and the positive charge on the proteins. The nucleocapsid of a naked helical virus is rigid and tightly wound into a cylinder-shaped structure. An example is the well-studied tobacco mosaic virus, an ssRNA virus that infects primarily tobacco plants and other members of the Solanaceae family (Figure 7.4). Enveloped helical nucleocapsids are more flexible and this type is found in several human viruses such as influenza and measles viruses.

FIGURE 7.4 Structure of the tobacco mosaic virus.
The capsomere of this naked helical virus is rigid and tightly wound into a cylinder-shaped structure.

Icosahedral Viruses

Capsids of many virus families are multifaced structures known as icosahedrons. These are three-dimensional, geometric figures with 12 corners, 20 triangular faces, and 30 edges (Figure 7.5). This icosahedral capsid symmetry results in a spherical appearance of viruses at low magnification. The arrangement of the capsomeres varies between the viruses and the shape and dimension of the icosahedron depend on the characteristics of its protomeres. Although the basic symmetry of icosahedral viruses is the same there are major variations in the number of capsomeres, and therefore differences in the size of the viruses. The basic triangular face of a small virus is constructed of 3 protomeres, with 60 of these subunits forming the whole capsid. For example, the poliovirus has 32 capsomeres, whereas an adenovirus has 240 capsomeres. During the assembling of an icosahedral virus the nucleic acid is packed into the center, forming a nucleocapsid. Icosahedral viruses can be naked, such as the adenovirus, or enveloped, as the herpes simplex virus (Figure 7.6). Included in this morphological group are the Iridoviridae (infect mainly invertebrates), Herpesviridae, Adenoviridae, Papovaviridae, and Parvoviridae.

FIGURE 7.5 Icosahedral virus.
The capsids of these viruses are called *icosahedrons*: three-dimensional, geometric figures with 12 corners, 20 triangular faces, and 30 edges.

FIGURE 7.6 Naked and enveloped icosahedral viruses.

Enveloped Viruses

Many viruses have an outer structure, the viral envelope, which surrounds the nucleocapsid. Enveloped viruses typically obtain their envelope by budding though a host plasma membrane (see Plasma Membrane in Chapter 3, Cell Structure and Function) but may also include some viral glycoproteins. In some cases the viral envelope is derived from other membranes in the host cell, such as from the membranes of the endoplasmic reticulum or the nuclear membrane. The creation of the viral envelope through the budding process allows the viral particles to leave the host cell without disrupting the plasma membrane and therefore without killing the cell. As a result, some budding viruses can set up persistent infections.

During the formation of the envelope some or all of the host membrane proteins are replaced by viral proteins and some form a layer between the capsid and the envelope. These envelope proteins are glycoproteins; they are exposed to the outside of the envelope as spikes. The lipid bilayer of the envelope is exclusively host specific whereas the majority or all of the glycoproteins are virus specific. The glycoproteins on the surface of the envelope serve to identify and bind to receptor sites on the plasma membrane of the host. Parts of the viral capsid and/or envelope are also responsible for stimulating the immune system of the host to produce antibodies that can neutralize the virus and prevent further infection (see Chapter 20, The Immune System). The viral envelope can give a virion protection from certain enzymes and chemicals; however, because enveloped viruses depend on their intact envelope to be infectious, agents that damage the envelope, such as alcohol and detergents, greatly reduce the infectivity of the virus (see Chapter 19, Physical and Chemical Methods of Control). An example of an enveloped virus is the influenza virus shown in Figure 7.7.

FIGURE 7.7 Influenza virus.
An example of an enveloped virus with two different types of spikes: hemagglutinin (H) and neuraminidase (N).

Complex Viruses

Complex viruses are a special group of viruses that consist of a capsid that is neither purely helical nor completely icosahedral and that has extra structures such as protein tails or a complex outer wall. The poxviruses are large, complex DNA viruses with an unusual morphology. These viruses lack a regular capsid and the viral genome is associated with proteins within a central disk structure, the nucleoid, which is surrounded by a membrane and two lateral bodies. The nucleoid is surrounded by several layers of lipoproteins and a coarse surface of fibrils (Figure 7.8, A).

An even more complex group of viruses are bacteriophages, viruses that infect bacteria. In general, bacteriophages have an icosahedral head bound to a polyhedral tail, which is attached to a base plate with many protruding protein tail fibers (Figure 7.8, B). Most bacteriophages contain double-stranded DNA (dsDNA); however, ssDNA- and RNA-type phages also exist. There are at least 12 separate groups of bacteriophages (Table 7.1), which are structurally and genetically diverse. Probably the most widely studied bacteriophages are the ones that infect Escherichia coli, a bacterium found in the normal flora of the intestinal tract (see Chapter 9, Infection and Disease). These bacteriophages are called coliphages and include the lambda phage and the T phages. Bacteriophages exist in different sizes and shapes, but the basic structural features are the same (Figure 7.9):

TABLE 7.1

Groups of Bacteriophages

Family or Group	Genus	Type Member	Particle Morphology	Envelope	Genome
Corticoviridae	Corticovirus	PM2	Isometric	No	Supercoiled dsDNA
Cystoviridae	Cystovirus	ϕ6	Isometric	Yes	Three segments, dsRNA
Inoviridae	Inovirus	Coliphages fd	Rod	No	Circular ssDNA
Inoviridae	Plectrovirus	Acholeplasma phage	Rod	No	Circular ssDNA
Leviviridae	Levivirus	Coliphage MS2	Icosahedral	No	1(+)strand (+)ssRNA
Leviviridae	Allolevirus	Coliphage Qbeta	Icosahedral	No	1(+)strand (+)ssRNA
Lipothrixiviridae	Lipothrixvirus	Thermoproteus phage 1	Rod	Yes	Linear dsDNA
Microviridae	Microvirus	Coliphages ϕX174	Icosahedral	No	Circular ssDNA
	Spirovirus	Spiroplasma phages
		Mac-1 phage
Myoviridae		Coliphages T4	Tailed phage	No	Linear dsDNA
Plasmaviridae	Plasmavirus	Acholeplasma phage	Pleomorphic	Yes	Circular dsDNA
Podoviridae		Coliphage T7	Tailed phage	No	Linear dsDNA
Siphoviridae	Lambda phage group	Coliphage lambda	Tailed phage	No	Linear dsDNA
Sulfolobus Shibatae virus		SSV-1	Lemon shaped	No	Circular dsDNA
Tectiviridae	Tectivirus	Phage PRD1	Icosahedral	No	Linear dsDNA

dsDNA, Double-stranded DNA; dsRNA, double-stranded RNA; ssDNA, single-stranded DNA.

FIGURE 7.9 Basic structure of a bacteriophage.
Bacteriophages, although different in size and shape, all have a capsid that contains the nucleic acid. Many bacteriophages also have a complex tail that enables the bacteriophage to attach to the host and inject the nucleic acid.

• Head or Capsid: All bacteriophages possess a head structure that varies in size and shape. It is made of many copies of one or more different proteins and the nucleic acid is located within this structure. The head or capsid therefore acts as the protective covering for the nucleic acid.

• Tail: Many bacteriophages have tails attached to the head, whereas others do not. The tail is a hollow tube that serves as a channel for the nucleic acid to pass through during the process of infecting a bacterium. Its size also varies depending on the phage type. Some of the more complex phages have a tail that is surrounded by a sheath, which contracts during infection of the bacterium. These phages also have a base plate at the end of the tail, with one or more tail fibers attached to it. The base plate and tail fibers play a major role in binding of the bacteriophage to the bacterium. Phages without base plate and tail fibers have other structures involved in binding of the phage to the bacterium.

MEDICAL HIGHLIGHTS

Avian Influenza in Humans

Although the avian influenza A viruses usually do not infect humans, the World Health Organization (WHO) has recently reported that the virus (H5N1) jumped the species barrier from birds to mammals, including humans. Infections in humans are rare and most occurred after direct contact with infected poultry. In humans, clinical symptoms due to the avian influenza A virus range from conjunctivitis to severe respiratory disease to death. Scientists warn that through mutation or recombination with other influenza viruses, this virus could acquire the ability to spread throughout the human population by person to person contact, resulting in a pandemic disease.

Almost 400 cases of human infection with the H5N1 virus have been reported between November 2003 and June 2008. The WHO maintains situation updates and cumulative reports of human cases of avian influenza A on their website, http://www.who.int/csr/disease/avian_influenza/en/

Viral Multiplication

Viruses are acellular organisms and do not replicate through cell division; instead they use host cell machinery and metabolism to produce multiple copies of themselves. Outside the host cell a virus is an inert particle. Host cells for each class of viruses are species specific and often even tissue specific.

Multiplication of Bacteriophages

A bacteriophage (or simply phage) is a virus that infects bacteria and multiplies inside of them. Just like bacteria, bacteriophages are common in all natural environments and their presence is directly related to the numbers of bacteria present. Knowledge of the phage life cycle is necessary to understand one of the mechanisms by which bacterial genes can be transferred from one bacterium to another. Bacteriophages are often used in diagnostic laboratories for the identification of pathogenic bacteria through phage typing, because each phage is highly specific for the bacterium it will invade. Bacteriophages can contain either DNA or RNA as its nucleic acid and the size of the nucleic acid varies depending on the phage. A simple phage might contain only enough nucleic acid to code for 3 to 5 average-sized gene products whereas others may code for more than 100 gene products. Therefore the number of different kinds of proteins and the amount of each will vary depending on the bacteriophage.

The events that occur in the multiplication cycle of bacteriophages include adsorption, penetration, replication, assembly, maturation, and release. Adsorption represents the recognition process between phage and bacterium, followed by attachment and then penetration of the phage DNA into the bacterium. Replication represents copying of phage nucleic acid, followed by the assembly of phage parts and maturation of the newly formed bacteriophages. The mature phages are then released from the host cell and are ready to infect others. These events are shown in Figure 7.10.

FIGURE 7.10 Multiplication of bacteriophages.

Adsorption

In the first step of successful bacterial infection, a phage must find a susceptible host and attach to the bacterial cell. This adsorption is mediated by the tail fibers (or analogous structures on phages without tail fibers), which bind to specific receptors on the bacterial cell surface. Bacterial structures that act as phage receptors include surface molecules of the cell wall, pili, and flagella. The host specificity of the phage is commonly determined by the type of tail fibers of the phage. This first step of attachment of the bacteriophage to the bacterium by the tail fibers is weak and reversible. The second step is irreversible binding of the phage to the bacterium. It is mediated by components of the base plate or by alternative ways in use by bacteriophages that lack these base plates. This firm attachment to the bacterium is irreversible and the phage is positioned for penetration.

Penetration

After the irreversible binding, the bacteriophage is still outside the bacterium and must inject its nucleic acid through the bacterial cell wall and into the cytoplasm of the host. Phages may have a contractile sheath that “constricts” after adsorption, pushing the inner tube through the cell wall of the bacterium and the cell membrane. This allows the phage’s nucleic acid to pass through the membrane and enter the bacterial cell. Bacteriophages without a contractile sheath use other mechanisms, such as digestion of portions of the bacterial cell wall, to gain access to the cytoplasm. In general, only the nucleic acid enters the host cell; the rest of the phage remains outside the bacterium. Penetration by some DNA bacteriophages that attach to pili, rather than to the cell wall, results in both the genomic DNA and capsid entering the cytoplasm of the host cell.

Assembly

Once the phage nucleic acid has entered the bacterium the bacterial metabolism shifts to the genetic expression of the viral nucleic acid strand and does not synthesize its own molecules. This change in metabolic activity of the host cell results in the formation of viral molecules such as the following:

• Proteins that seal the damaged bacterial cell wall to prevent premature bacterial cell death

• Enzymes that are necessary to copy the genome of the bacteriophage

• Proteins that are needed for the formation of the capsid head and part of the tail fibers

• Enzymes required for the weakening of the bacterial cell wall in order to lyse the bacterial cell and release the newly assembled bacteriophages

The multiplication of bacteriophages can either result in the lysis (“bursting”) of the infected bacterium or in a silent viral infection referred to as lysogeny.

• Lytic or virulent phages are phages that after multiplication destroy the bacterium by lysis at the end of the multiplication cycle, releasing the newly formed phages into the environment. This lytic life cycle can be divided into three phases: the eclipse period, the intracellular accumulation phase, and the lysis and release phase.

• Eclipse period: In this phase no infectious phage particles can be found in the host cell. The viral synthesis process utilizes the resources of the host and the phage nucleic acid takes over the biosynthetic machinery to produce phage specific mRNA’s to make proteins. In the early phase of this period, early mRNA’s code for proteins which are needed for the synthesis of phage DNA and synthesis of host DNA, RNA and proteins come to an end. After the production of phage DNA late mRNAs and their corresponding proteins are made. These late proteins are structural proteins for the phages and also proteins necessary for the lysis of the host cell.

• Intracellular accumulation phase: The nucleic acids and the structural proteins made in the previous phase are assembled into complete infectious phages that accumulate in the host cell.

• Lysis and release phase: During this phase the bacteria begin to lyse, due to the accumulation of phage lysis proteins, and the phages are released into the environment surrounding the bacterium. Infected bacteria may release up to 1000 bacteriophages.

• Lysogenic or temperate phages are those that can either multiply by the lytic cycle or undergo adsorption and penetration into the bacterial host but are not replicated or released at that time. Instead the phage genes are not transcribed, and the phage genome exists in a repressed state. The phage DNA in this stage is referred to as a prophage, because it is not a phage but has the potential to produce a phage. In general, the bacteriophage DNA is integrated into the host chromosome and passed on to the daughter cells of the bacterium. The host cell carrying a prophage might not be adversely affected at all and the lysogenic state might persist indefinitely or eventually result in lysis. Lysogeny is a less deadly form of parasitism, allowing the virus to spread without killing the host. On occasion the prophage in a lysogenic cell can be activated, which ultimately results in viral replication and the lytic cycle.

MEDICAL HIGHLIGHTS

Therapeutic Bacteriophages

The term “therapeutic bacteriophages” describes the therapeutic use of lytic bacteriophages for the treatment of pathogenic bacterial infections. In general, the host range of bacteriophages is narrower than that of antibiotics used in the clinical environment. Most bacteriophages are specific for one species of bacteria and may only lyse a specific strain within a species. Many bacteria become resistant to all available antibiotics and cause serious problems in the form of untreatable infections, such as some hospital-acquired infections (see Chapter 9, Infection and Disease), and the basis for possible epidemics.

Phage therapy was first developed in the early 1900s but, because of the emergence of antibiotics in 1941, the Western world shifted interest away from the further use and study of phage therapy. Because of their isolation from Western advances in antibiotic production, Russian scientists continued to develop the already successful phage therapy to treat the wounds of soldiers in field hospitals. As a result, extensive clinical research and implementation of phage therapy continued in Eastern Europe.

In 2006, a biopharmaceutical company (GangaGen, Inc.) began developing phage technology for the treatment of antibiotic-resistant bacterial infections and was awarded a U.S. patent for the invention of “lysin-deficient bacteriophages having reduced immunogenicity” for use in the destruction of pathogenic bacteria, including those resistant to antibiotics. This patent provides an opportunity for phage therapy to be used in both human and veterinary medicine.

Multiplication of Animal Viruses

The basic stages of multiplication of animal viruses are similar to those seen in bacteriophages. However, several differences are present between the host cells, their viruses, and also in some steps of the multiplication cycle. The stages of the multiplication cycle for animal viruses include adsorption, penetration, uncoating, replication, assembly, and finally release from the host cell. The duration of the multiplication cycle varies among animal viruses. The basic stages of the cycle in naked and enveloped viruses are shown in Figure 7.11.

FIGURE 7.11 Multiplication of naked animal viruses.

Adsorption

The first stage of multiplication is the attachment (adsorption) of the virus to a susceptible host cell. Like bacteriophages, animal viruses are specific to their host cells and they infect only one or a restricted range of host species. This limitation is referred to as the host range. For example, hepatitis viruses attack cells in the liver, the mumps virus attacks the salivary glands, and HIV attaches to the CD4 protein of helper T cells (see Chapter 20, The Immune System). They adsorb to specific receptor sites embedded in the plasma membrane of their host, which are generally glycoproteins the host cell requires for its normal cellular functions. The attachment sites on the virus (viral receptors) are distributed over the capsid or envelope of the virus and are generally glycoproteins or proteins. Animal cells that lack receptors for a specific virus are resistant and cannot be infected by that virus. Naked and enveloped viruses differ in their mode of attachment to the host cell. Naked viruses have surface molecules that adhere to the membrane receptor, whereas enveloped viruses possess glycoprotein spikes that bind to the plasma membrane receptors of the host cells (Figure 7.12). The attachment of a virus to its host can be prevented by antibody molecules that are capable of attaching to the viral attachment sites or to the host cell receptors. The presence of these antibodies in the host organism is the most important basis for immunity against viral infections (see Chapter 20).

FIGURE 7.12 Multiplication of enveloped animal viruses.

Penetration

After the adsorption stage is the penetration of the virus into the cytoplasm of the host, either via endocytosis (engulfment) of the whole virus or by fusion of the viral envelope with the plasma membrane, allowing only the nucleocapsid of the virus to enter the cell. Unlike bacteriophages, animal viruses generally do not “inject” their nucleic acid into the host cells; however, on occasion nonenveloped viruses leave their capsid outside the cell while the genome passes into the cell.

Uncoating

When the nucleocapsid is in the host cell cytoplasm the viral nucleic acid is released by a process called uncoating. The uncoating process varies between viruses. If penetration occurs by receptor-mediated endocytosis (see Chapter 3, Cell Structure and Function) the entire virus is engulfed by the host cell and becomes enclosed in a vacuole or vesicle. The enzymes in the vacuole or vesicle then dissolve the envelope and the capsid, and the viral genome is released. Another method of entry occurs by direct fusion of the viral envelope with the plasma membrane of the host cell, thereby releasing the nucleocapsid into the cell cytoplasm. Some antiviral drugs (see Chapter 22, Antimicrobial Drugs) exert their effect by preventing the uncoating of the nucleocapsid.

Replication

Synthesis and replication of animal viruses occur immediately after the uncoating process. This phase is highly regulated, complex, and the events proceed depending on whether the nucleic acid of the infecting virus is DNA or RNA.

In the case of DNA viruses, the viral DNA enters the nucleus of the host cell where it is transcribed into early mRNA, which leaves the nucleus and enters the cytoplasm. The early mRNA is then translated into early viral proteins. The early viral proteins deal with the replication of viral DNA and therefore are transported back into the nucleus. Once in the nucleus these proteins become involved in the synthesis of multiple copies of viral DNA, using host DNA polymerase. The copies of the viral genome then act as templates for transcription into late mRNA which leaves the nucleus for translation into late viral proteins in the cytoplasm. The late proteins are structural proteins such as coat and envelope proteins, or core proteins such as enzymes that are transported back into the nucleus for the next stage of the replication phase.

RNA viruses cannot be transcribed in the same manner as DNA viruses, because the host polymerases do not work for RNA. In other words, the RNA virus must provide its own polymerase if transcription is necessary. In the case of dsRNA viruses, one strand is first transcribed by viral polymerase into mRNA. Three separate routes for the formation of mRNA occur in ssRNA viruses:

• An ssRNA with a positive-sense configuration can be used directly as mRNA.

• An ssRNA with a negative-sense configuration must first be transcribed into a positive-sense strand by viral polymerase and can then be used as mRNA.

• Retroviruses use a different route. These viruses have a positive-sense ssRNA that is made into a negative-sense ssDNA, using viral reverse transcriptase present in the nucleocapsid. This process is followed by the formation of dsDNA, which enters the nucleus and becomes integrated into the host DNA. The integrated viral DNA is then transcribed by host polymerase into mRNA.

In all three cases, translation of the viral mRNA occurs at the host ribosomes, producing viral proteins for the final assembly of the virus. In addition to viral protein synthesis the virus must also replicate its nucleic acid. In the early phase the proteins produced are enzymes and regulatory molecules that will allow subsequent replication of viral nucleic acid. The late phase deals with the synthesis of proteins necessary for capsid formation.

Assembly

Once the synthesis of the viral components is complete the assembly phase begins. In this phase, mature viral particles are constructed from a growing quantity of viral components. Commonly, the capsid is produced first as an empty shell that serves as a container for the nucleic acid. This process is called encapsidation.

Release

The final phase of viral multiplication is the release stage, which results in the exit of mature virions from the host cell. This process occurs in one of two ways: budding (exocytosis) or cell death (lysis). Nonenveloped viruses mature in the nucleus or cytoplasm and are released when the cell ruptures or lyses. Enveloped viruses, on the other hand, are discharged by budding from:

• The plasma membrane

• The nuclear membrane

• The endoplasmic reticulum

• Or by vesicular formation, without cell death

The nucleocapsid binds to the membrane, which curves around the particle, forming a small pouch (envelope). Whenever a virus uses a host membrane to exit the cell, it always inserts into the envelope specific viral proteins, which represent specific viral antigens. These antigens are used by the virus to gain access into a new host cell. Furthermore, the insertion of viral molecules into the host plasma membrane alters the host cell, resulting in an antigenically different cell. This expression of viral antigens is a major factor in the development of antiviral immune responses.

Although budding of enveloped viruses causes them to be shed gradually over a period of time without sudden cell death, most active viral infections are ultimately lethal to the cell because of cumulative damage caused by the virus.

Viral Infections

The short- and long-term effects of viral infections in animal cells are well documented and viral infections can have the following outcomes:

• Abortive infections are infections of nonpermissive cells where no viral production occurs.

• Lytic or cytocidal infections kill the host cell. This type of infection occurs in permissive cells, cells that provide the biosynthetic machinery to support the complete replication cycle of the virus.

• Persistent infections are infections that do not cause cell death. They can be:

• Chronic infections that are not lytic but productive. The cellular effects of chronic infections are mostly the same as in acute cytocidal infections with the exception that the production of viruses may be slower, intermittent or limited to only a few cells.

• Latent infections with limited macromolecular synthesis but no virus synthesis. In other words, only restricted expression of the viral genome occurs. The viral gene products are associated with few if any changes in the infected cell.

• Slow infections, characterized by a prolonged incubation period without prominent morphological and physiological changes to the host cell. Although the progression of cellular damage may take years, it is followed by extensive cellular injury and disease.

• Transforming infections, in which the viral nucleic acid may remain in specific host cells indefinitely, and a virus may or may not be produced. The term oncogenic transformation refers to the genetic modification of cell proliferation control so that the cell becomes cancerous. DNA or RNA tumor viruses may initiate several changes that convert normal cells into malignant tumor cells (see Genotoxic Effects later in this chapter). Infected cells may also undergo other types of inheritable changes resulting in morphological, physiological, and biochemical alterations that are nononcogenic. In other words, if a virus infects a cell and alters the properties of that cell, the cell is referred to as transformed.

Host Cell Damage

A viral infection is usually associated with changes in the cell morphology, physiology, and biosynthetic events.

Morphological Effects

Changes in the morphology of a host cell caused by viral infections are referred to as cytopathic effects. Cytopathic effects (CPEs) include the following:

• Altered shape (i.e., rounding of cells)

• Detachment from tissue surface

• Lysis

• Membrane fusion

• Altered membrane permeability

• Inclusion bodies (either altered host cell structure or accumulation of viral components)

• Apoptosis (programmed cell death)

The specific cytopathic effects caused by different viruses depend on the viruses and the cells they infect. The observations of cytopathic effects can be used in clinical virology to aid in the identification of a viral isolate. Cytopathic changes of selected viruses are listed in Table 7.2.

TABLE 7.2

Cytopathic Effects of Selected Viruses

Virus	Cytopathic effect
Adenovirus	Nuclear inclusions; cell clumping
Herpes simplex virus	Cell fusion leading to multinucleated giant cells; nuclear inclusions
HIV	Multinucleated giant cells
Influenza virus	Rounding of cells
Poliovirus	Cell lysis
Rabies virus	Cytoplasmic inclusions: Negri bodies
Reovirus	Cell enlargement; vacuoles and inclusion bodies in cytoplasm
Smallpox virus	Rounding of cells; cytoplasmic inclusions

Physiological Effects

Interaction of a virus with the plasma membrane or intracellular membranes and any subsequent events, such as the addition of viral proteins, can change the physiological characteristics of the host cell. This may include the movement of ions, formation of secondary messengers, and launching of activities that lead to altered cellular activities. Viral proteins incorporated into the plasma membrane of the host cell may also alter its antigenic or immune properties.

Biochemical Effects

A large number of viruses inhibit or alter synthesis of the infected cells’ own macromolecules, such as DNA, RNA, and various proteins. Cellular transcription and protein-to-protein interactions may also be altered to promote the production of new viruses. Furthermore, some viruses may stimulate specific cellular biochemical activities in order to increase virus replication.

Genotoxic Effects

Genotoxic substances damage DNA either directly, by binding to the DNA, or indirectly leading to DNA damage by affecting enzymes involved in DNA replication. These substances therefore cause mutations, which may or may not lead to cancer. After a viral infection, breakage, fragmentation, rearrangement, or other changes in the host DNA may occur. Double-stranded DNA viruses interact directly with the host DNA and in some cases the viral DNA becomes integrated at a particular site in the host genome. All parts of the viral genome are expressed in permissive cells, which leads to viral replication, lysis, and cell death. When the viral DNA becomes integrated into the host genome at random sites in nonpermissive cells, only part of the viral genome is expressed. In this case the early control functions of the virus are expressed, while viral structural proteins are not produced. Several DNA viruses such as the hepatitis B virus, the herpesviruses, and the papillomaviruses are potentially initiators of cancer. RNA tumor viruses (retroviruses) usually change cells into malignant cells by integrating their own nucleic acid into the host cell genome and may even produce infectious new viruses. Because RNA is the genome of the mature viral particle it must first be copied to DNA (see Viral Multiplication earlier in this chapter) before integration into the host DNA.

HEALTHCARE APPLICATION
Oncogenic Viruses and Associated Cancers

Virus	Nucleic Acid	Disease	Cancer
Papovaviridae Papillomavirus (some)	dsDNA	Warts, genital warts	Cervical cancer
Herpesviridae Lymphocryptovirus (Epstein-Barr virus)	dsDNA	Infectious mononucleosis	Burkitt’s lymphoma; nasopharygeal carcinoma; may play a role in the development of Hodgkin’s disease
Herpesviridae Herpes simplex virus (HSV-2, HSV-8)	dsDNA	Genital herpes	Cervical cancer Kaposi’s sarcoma
Hepadnavirus Hepatitis B virus	dsDNA	Hepatitis B	Liver cancer
Adenoviridae	dsDNA	Acute respiratory disease; common cold	Adenocarcinomas
Poxviridae	dsDNA	Smallpox; cowpox	Miscellaneous
Retroviridae	ssRNA	Adult T-cell leukemia; HIV infections	Adult T-cell lymphoma; AIDS

Major Groups of Viruses in Vertebrates

Vertebrate viruses cause disease after they break the natural protective barriers and gain access to underlying tissues and organs. Most viruses are specific to a particular cell or tissue type, but a particular disease may be caused by several viruses that have a common tissue preference. The genome of viruses can consist of either DNA or RNA.

DNA Viruses

Adenoviruses

Adenoviruses belong to the family Adenoviridae and most commonly cause respiratory illness. There are 49 immunologically distinct human adenoviruses and, depending on the serotype, they may also cause various other illnesses including gastroenteritis, conjunctivitis, cystitis, and rashes. The symptoms caused by adenovirus-induced respiratory illnesses range from common cold symptoms to pneumonia, croup, and bronchitis. In children adenoviruses typically cause respiratory and gastrointestinal tract infections. Immunocompromised patients are especially vulnerable and susceptible to severe complications of adenoviral infections.

Adenoviruses are linear dsDNA viruses of medium size (90–100 nm), are nonenveloped, and have an icosahedral nucleocapsid. The viruses are unusually stable to chemical or physical agents and also to adverse pH conditions. This allows the virus to survive outside of the human body for prolonged periods of time.

Hepadnaviruses

Hepadnaviruses are part of the family Hepadnaviridae and cause hepatitis in humans and animals. These viruses are enveloped virions with a small circular genome of partially double-stranded and partially single-stranded DNA. When the virus enters the host cell, the single-stranded portion is restored to a double strand by a DNA polymer present in the core. One member of the group is the hepatitis B virus (HBV), which infects hepatocytes where it can persist, causing hepatitis, and can also be a factor in liver cell carcinoma. HBV can cause acute or chronic, symptomatic or asymptomatic disease (see Chapter 12, Infections of the Gastrointestinal System).

Herpesviruses

Herpesviruses (Herpesviridae) are a large family of DNA viruses that cause disease in humans and animals. The human herpesviruses are grouped into three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. This classification is based on differences in viral characteristics such as genome structure, tissue tropism, cytopathology, and site of latent infection, as well as pathogenesis of the disease (Table 7.3). The human herpesviruses are as follows:

TABLE 7.3

Characteristics of Herpesviridae

Subfamily	Virus	Pathophysiology	Transmission
Herpesdviridae
Human herpesvirus 1	Herpes simplex virus 1 (HSV-1)	Oral and/or genital herpes (primarily orofacial)	Close contact
Human herpesvirus 2	Herpes simplex virus 2 (HSV-2)	Oral and/or genital herpes (predominantly genital)	Sexually transmitted
Human herpesvirus 3	Varicella-zoster virus (VZV)	Chickenpox and shingles	Respiratory and close contact
Gammaherpesvirinae
Human herpesvirus 4	Epstein-Barr virus (EBV), lymphocryptovirus	Infectious mononucleosis, Burkitt’s lymphoma, CNS lymphoma in AIDS patients, posttransplant lymphoproliferative syndrome, nasopharyngeal carcinoma	EBV: saliva (kissing disease)
Human herpesvirus 8	Kaposi’s sarcoma–associated herpesvirus	Kaposi’s sarcoma, primary effusion lymphoma, some types of multicentric Castleman’s disease	Close contact (sexual), saliva?
*Betaherpesvirinae*
Human herpesvirus 4	Cytomegalovirus	Infectious mononucleosis, retinitis, etc.	Close contact, transfusions, tissue transplant, congenital
Human herpesvirus 6 Human herpesvirus 7

Roseolovirus Sixth disease (roseola infantum or exanthema subitum) Respiratory and close contact?

• Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2)

• Varicella-zoster virus (VZV)

• Epstein-Barr virus (EBV)

• Cytomegalovirus (CMV)

• Human herpesviruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8)

The herpesviruses are large enveloped dsDNA (linear) viruses that acquire their envelope by budding from nuclear and plasma membranes of the host cell. They replicate in the nucleus of infected cells and characteristically demonstrate latency, which allows them to exist in a dormant stage for the duration of the host tissue’s lifetime. When activated they cause recurrent disease in their hosts (e.g., varicella-zoster virus; see Chapter 10, Infections of the Integumentary System, Soft Tissue, and Muscle). Reactivation of the viruses can occur in response to environmental changes such as ultraviolet light, x-rays, heat, cold, hormonal changes, stress (both physical and emotional), and immune deficiencies.

Papillomaviruses and Polyomaviruses

Papillomaviruses and polyomaviruses were previously grouped in the family Papovaviridae, but have been divided into two families, the Papillomaviridae and Polyomaviridae. Both families can cause host-dependent lytic, chronic, latent, and transforming infections. Papillomaviruses and polyomaviruses are small nonenveloped viruses with circular dsDNA and an icosahedral capsid. Human papillomaviruses cause warts and several types are associated with cancer such as cervical carcinomas.

Parvoviruses

Parvoviridae species are the smallest of the DNA viruses (18 to 26 nm in diameter), and only one member, the B19 agent, is known to infect human cells. All other members are best known for their capacity to cause disease in animals. The parvoviruses have a nonenveloped, icosahedral capsid and the B19 virus genome contains one linear, ssDNA molecule. The B19 virus prefers to replicate in mitotically active cells such as human bone marrow cells, erythroid cells, and erythroid leukemia cells. B19 is the agent of contagious erythema infectiosum, commonly called fifth disease, because of the development of a face rash similar to the other four diseases, measles, rubella, scarlet fever, and Dukes’ disease.

Poxviruses

Poxviruses are the largest viruses, about 200 nm in diameter and 300 nm in length, with very complex nucleocapsid symmetry. They vary in shape depending on the species, but for the most part they are brick shaped or in oval form, similar to a rounded brick. The viral genome is a large double-stranded linear DNA, fused at both ends. The human poxviruses include variola (genus Orthopoxirus), the causative agent for smallpox, and molluscum contagiosum (genus Molluscipoxvirus), which can cause benign tumors in humans.

The vaccinia virus, another poxvirus related to the smallpox virus, is the “live virus” used in the smallpox vaccine. When given to humans as a vaccine it will help the body to develop immunity to smallpox. The vaccinia virus is best known for the eradication of smallpox, which was announced by the World Health Organization in 1980.

LIFE APPLICATION

Smallpox as Biological Weapon

Smallpox is believed to have originated more than 3000 years ago in India or Egypt, and it is one of the most devastating diseases known to mankind. While effective treatment of the disease has never been developed, Edward Jenner discovered that inoculation with cowpox could protect humans against smallpox. The development of the first live vaccine against small pox in 1796, and its later worldwide distribution, led to the eradication of the smallpox (variola) virus in 1980, resulting in the destruction of reference stocks in the World Health Organization laboratories. However, the virus did not disappear and stocks still exist in the United States and Russia. The natural smallpox virus was successfully eliminated, but the former Soviet Union was stockpiling large amounts of the smallpox virus for use in biowarfare. The U.S. Centers for Disease Control and Prevention (CDC) considers smallpox a category A agent together with anthrax, plague, botulism, tularemia, and viral hemorrhagic fever. These agents have great potential in bioterrorism-biowarfare if acquired by terrorists and/or hostile nations. All these agents could be widely distributed causing serious disease outbreaks. This potential threat has renewed interest in developing new smallpox vaccine programs and programs dealing with the development of potent antiviral drugs.

RNA Viruses

Bunyaviridae

Bunyaviridae species are enveloped viruses with a large negative-stranded RNA as their nucleic acid. They are zoonoses and while generally found in animals, certain members in this family can infect humans (Table 7.4). Bunyaviridae comprises a group of at least 200 viruses broken down into five genera based on structural and biochemical features: Bunyavirus, Phlebovirus, Uukuvirus, Nairovirus, and Hantavirus. With the exception of the hantavirus, which is carried by rodents, Bunyaviridae species are arthropod-borne.

TABLE 7.4

Examples of Bunyaviridae Capable of Infecting Humans

Genus	Insect Vector	Vertebrate Host	Human Pathology
Bunyavirus	Mosquito	Rodents, small mammals, primates, birds, marsupials	Febrile illness, encephalitis
Hantavirus	None	Rodents	Hemorrhagic fever with renal syndrome, adult respiratory distress syndrome, hantavirus pulmonary syndrome, shock, pulmonary edema
Nairovirus	Tick	Hares, cattle, goats, seabirds	Hemorrhagic fever
Phlebovirus	Fly	Sheep, cattle, domestic animals	Rift Valley fever, sandfly fever, hemorrhagic fever, encephalitis, conjunctivitis, myositis

Coronaviruses

Coronaviruses belong to the family Coronaviridae and are cataloged as Group IV of the Baltimore classification system. These viruses are between 80 to 160 nm in diameter, which makes them the largest of the RNA viruses. Coronaviruses are enveloped with a (+) ssRNA genome and helical symmetry. They infect humans and animals, causing respiratory and enteric diseases. The coronaviruses are the second most prevalent cause of the common cold, the rhinovirus being the most common one.

The severe acute respiratory syndrome (SARS) is caused by the coronavirus SARS-CoV (see Chapter 11, Infections of the Respiratory System, and Chapter 18, Emerging Infectious Diseases).

Hepatitis Viruses

Many of the liver diseases, collectively called hepatitis, are caused by viruses, coming from a wide range of viral families (Table 7.5). Each of the hepatitis viruses infects and damages the liver, causing jaundice and the release of liver enzymes. Viral hepatitis is a cause of considerable morbidity and mortality in the human population, both from acute and chronic infection, including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Viral hepatitis is a major public health problem throughout the world, affecting several hundreds of millions of people.

TABLE 7.5

Hepatitis Viruses

Virus	Subfamily	Structure	Transmission
Hepatitis A	Picornavirus	Positive-sense RNA, unenveloped icosahedral capsid	Fecal–oral route, water- or foodborne
Hepatitis B	Hepadnavirus	Enveloped DNA	Paternally by blood or needles, sexual contact, perinatally
Hepatitis C	Flavivirus	Positive-strand RNA, enveloped	Blood-to-blood contact, infected blood, intravenous drug abuse, sexually, transfusion and organ recipients
Hepatitis D	Delta agent (virus)	Negative-sense, single-stranded, closed circular RNA	Needs hepatitis B virus to exist, found in persons infected with the hepatitis B virus
Hepatitis E	Herpesvirus	Nonenveloped, positive-sense, single-stranded RNA	Fecal–oral route, especially contaminated water

Orthomyxoviruses

Orthomyxoviruses belong to the family Orthomyxoviridae and include the influenza A, B, and C viruses. The viruses are enveloped with a segmented negative-sense RNA genome. Influenza A and C viruses infect multiple species, whereas influenza B infects mostly humans. Significant human disease is due only to influenza A and B viruses. The type A viruses are the most virulent human pathogens in this group and cause the most severe disease. Influenza viruses are respiratory viruses (see Chapter 11, Infections of the Respiratory System) responsible for the classic flulike symptoms of fever, malaise, headache, and body aches (myalgias). Influenza is one of the most prevalent of the viral infections. The segmented nature of the influenza virus genome makes the development of new strains possible through mutation and rearrangement of gene segments between human and animal strains of the virus. This genetic instability and the resulting emergence of new strains are responsible for the annual flu epidemics and periodic pandemics (see Chapter 18, Emerging Infectious Diseases). The prophylactic vaccines and antiviral drugs that are now available make it possible to prevent serious disease complications in people at risk. Example of known flu pandemics (worldwide) are given in Table 7.6.

TABLE 7.6

Known Flu Pandemics

Name of Pandemic	Date	Estimated Deaths
Asiatic (Russian) flu	1889–1890	1 million
Spanish flu	1918–1920	40 million
Asian flu	1957–1958	1 to 1.5 million
Hong Kong flu	1968–1969	0.75 to 1 million

Paramyxoviruses

Paramyxoviruses belong to the family Paramyxoviridae, which consists of three genera: Morbillivirus, Paramyxovirus, and Pneumovirus.

• Morbillivirus includes the measles viruses.

• Paramyxovirus includes the parainfluenza and mumps viruses.

• Pneumovirus includes the respiratory syncytial virus.

Paramyxoviruses have a (−) ssRNA genome, are highly pleomorphic and enveloped, with helical nucleocapsid symmetry. The Nipah virus and Hendra virus, zoonosis-causing viruses, are highly pathogenic paramyxoviruses identified in 1998 after outbreaks of severe encephalitis in Malaysia and Singapore. Protection can be provided for the measles and mumps viruses by an effective live vaccine used in the United States and other developed countries. Vaccination programs in these countries make the occurrence of measles and mumps rare.

Picornaviruses

Picornaviruses are viruses belonging to the family Picornaviridae. They are one of the largest families of viruses and are the smallest of the RNA viruses. Picornaviruses are nonenveloped viruses with icosahedral nucleocapsids containing a (+) ssRNA as their genome. This RNA is similar to mRNA and can either act as mRNA or can be a template for a replicate form. Picornaviruses are separated into nine distinct genera, with many of them important pathogens of humans and animals. They include Enterovirus, Rhinovirus, Hepatovirus, Cardiovirus, Aphthovirus, Parechovirus, Erbovirus, Kobuvirus, and Teschovirus.

Two main categories causing a variety of human infections are the enteroviruses and the rhinoviruses. They are distinctly different in the stability of their capsid at low pH as well as in their optimal temperature for growth. The capsid of enteroviruses is stable at the pH 3, which allows them to survive under harsh environmental conditions such as the gastrointestinal tract and sewer systems. They are transmitted by the fecal–oral route. In contrast, the rhinoviruses are acid labile; they infect primarily the nose and throat; and they grow best at 33° C (temperature of the nasal cavity). Enteroviruses replicate at 37° C. The portal of entry (see Chapter 9, Infection and Disease) can be the upper respiratory tract, the oropharynx, and the gastrointestinal tract. Most enteroviruses are cytolytic; they replicate rapidly and cause direct damage to the infected cells. In the case of poliovirus, the virus infects skeletal muscle and gains entry to the nervous system by traveling along the innervating nerve fibers (see Chapter 13, Infections of the Nervous System and Senses). Rhinoviruses are the most common initiators of the common cold and upper respiratory tract infections. There are 115 or more serotypes of rhinovirus; their infections are self-limiting and generally do not cause serious disease.

Rhabdoviruses

Members of the family Rhabdoviridae infect plants, insects, fish, birds, and mammals, including humans. Rhabdoviruses are simple viruses that carry their genome in the form of a (−) ssRNA. They encode only five proteins, are enveloped, and have a characteristic bullet-shaped appearance. The most significant pathogen of this group is the rabies virus, causing the almost invariably fatal disease called rabies. Until Louis Pasteur developed the rabies vaccine, a bite from a rabid animal always led to certain death. Although rare, it is possible that a person may contract rabies if infectious material from a rabid animal, such as saliva, gains entry directly though their eyes, nose, mouth, or a wound. For protective purposes the rabies vaccine is now given to people at high risk of exposure. People not vaccinated and who have been bitten by an animal or otherwise been exposed to rabies can receive vaccination after the exposure to prevent the disease.

Reoviruses

The name reovirus was given to a group of enteric and respiratory viruses not associated with a particular disease and were considered to be “respiratory, enteric, orphans.” Reoviruses are nonenveloped with an icosahedral nucleocapsid and a dsRNA genome. The virion is rather resistant to undesirable environmental and gastrointestinal conditions such as variations in pH and temperature, detergents, and drying. One of the genera of reoviruses is Rotavirus, the causative agent of human infantile gastroenteritis (see Chapter 12, Infections of the Gastrointestinal System), a common disease in children. The virus accounts for approximately 50% of all case of diarrhea in children requiring hospitalization because of dehydration. Rotaviral infections are a major problem in underdeveloped countries, where the virus is responsible for more than 1 million deaths per year. Rotaviruses are also one of the causes of “traveler’s” diarrhea.

Retroviruses

Retroviruses are classified according to the disease they cause, tissue tropism and host range, virion morphology, and complexity of the genome. The subfamilies of the human retroviruses are Oncovirinae, Lentivirinae, and Spumavirinae (Table 7.7). The viruses are enveloped, somewhat spherical in shape, and their genome consists of two identical copies of (+) ssRNA. These viruses have a unique replication cycle: they encode an RNA-dependent DNA polymerase (reverse transcriptase), which allows them to replicate through a DNA intermediate. The DNA copy of the viral genome, called a provirus, is then integrated into the host cell DNA and thereby becomes a cellular gene.

TABLE 7.7

Subfamilies of Retroviruses

Subfamily	Characteristics
Oncovirinae	Associated with cancer and neurological disorders
Type B	Unconventional nucleocapsid in mature virus
Type C	Centrally located nucleocapsid core in mature virion
Type D	Cylindrical nucleocapsid core
Lentivirinae	Slow disease onset: neurologic disorders and immunosuppression; are D-type viruses (cylindrical nucleocapsid core)
Spumavirinae	No clinical disease, but characteristic vacuolated “foamy” cytopathology
Endogenous viruses	Retrovirus sequence that can be integrated into the human genome

Togaviruses

Members of the family Togaviridae are enveloped (+) ssRNA viruses with icosahedral nucleocapsid symmetry. They include the genera Alphavirus and Rubivirus. Alphaviruses are found around the world and many of them are pathogenic to humans. The most common results of alphaviral infections include infectious arthritis, encephalitis, rashes, and fever. Alphaviruses are of interest in gene therapy research laboratories for the development of viral vectors for gene delivery.

Rubivirus contains only one recognized species, the rubella virus, and the causative agent of rubella (German measles). In contrast to the other togaviruses, rubella is a respiratory virus (see Chapter 11, Infections of the Respiratory System).

Flaviviruses

Flaviviruses are enveloped viruses with (+) ssRNA and icosahedral nucleocapsid symmetry, making them similar to togaviruses but they differ in their method of replication. Flaviviruses are the causative agents of yellow fever, encephalitis, Dengue fever, and hepatitis C.

Subviral Agents

Subviral agents are substances smaller than a virus but having some viral properties. These are unusual infectious agents with a characteristically small genome, and include viroids, virusoids (satellites), and prions.

Viroids

Viroids range in size from 15 to 100 nm in diameter, and their RNA genomes are 246 to 375 nucleotides in length. They are all single-stranded circles; replication does not depend on the presence of a helper virus, and no proteins are encoded. They are common plant pathogens causing serious economic problems. Although they do not have a protective protein coat around the nucleic acid, these naked RNA pathogens can cause disease in susceptible plants. These plants include potatoes, tomatoes, cucumbers, palm trees, and certain fruit trees. The current taxonomy of viroids is shown in Table 7.8.

TABLE 7.8

Classification of Viroids

Family (Subfamily)	Genus	Species	Hosts
Pospiviroidae	Pospiviroid Hostuviroid Cocadviroid Apscaviroid Coleviroid

Potato spindle tuber viroid

Hop stunt viroid

Coconut cadang-cadang viroid

Apple scar skin viroid

Coleus blumei viroid 1

Plants Avsunviroidae

Avsunviroid

Pelamonviroid

Avocado sunblotch viroid

Peach latent mosaic viroid

Plants

Virusoids (Satellites)

Virusoids or satellites RNAs have genomes from 220 to 388 nucleotides long, their genomes are circular and single stranded, and they have ribozyme activity. Virusoids replicate in the cytoplasm of their host, using an RNA-dependent RNA polymerase. Although the RNA replication is similar to that of viroids, virusoids require that the host cell be infected with a specific helper virus. Virusoids are generally associated with plant infections, but there are similar agents that infect animals. One of these agents infecting humans is the hepatitis delta virus (HDV). For hepatitis D virusoid to function, a cell must be simultaneously infected with the hepatitis B virus. However, there is a significant difference between viroids and HDV: viroids cannot produce proteins whereas HDV produces two proteins named small and large delta antigens.

Prions

Prions (proteinaceous infectious particles) are infectious agents that do not have a nucleic acid genome. Prions are normal proteins in animal tissue, but when these particles become abnormally folded and shaped they become proteinaceous infectious particles that are not cellular organisms or viral particles. In their noninfectious stage they are normal proteins involved in cell-to-cell communication. Once they become infectious prions and come in contact with physiological normally shaped proteins, these particles will transform the normal proteins into abnormally shaped prions. Prions are associated with a variety of neurodegenerative diseases with a slow onset and previously considered to be caused by slow viruses. Prion diseases are transmissible from host to host of a single species, or sometimes from one species to another. They destroy brain tissue, giving it a spongy appearance, and thus also referred to as the transmissible spongiform encephalopathies (TSEs), such as “mad cow disease.”

HEALTHCARE APPLICATION
Examples of Human Prion Diseases

Disease	Transmission	Clinical Signs and Symptoms	Treatment
Creutzfeldt-Jacob disease (CJD)	Spontaneous transformation of normal prion proteins; 10%–15% inherited (autosomal dominant)	Dementia Early neurologic signs: Periodic waves on the electroencephalogram (EEG); presence of “florid plaques” on neuropathology; presence of agent in lymphoid tissue	None known; rapidly progressive and always fatal
Variant Creutzfeldt-Jacob disease (vCJD)	“Mad cow” disease: Contracted when exposed to food contaminated with bovine spongiform encephalopathy (BSE)	Prominent psychiatric/behavioral symptoms; painful dyesthesiasis (distortion of the sense of touch); delayed neurological signs; large amounts of “florid plaques” on neuropathology	Supportive: No specific treatment; fatal
Gerstmann-Sträussler-Scheinker syndrome	Inherited	Various levels of ataxia; dysarthria (slurring of speech), dementia, nystagmus, spasticity, visual disturbances	No cure, no known treatment, only supportive
Kuru	Cannibalism	Unsteady gait, tremors, slurred speech	No cure, no treatment, only supportive