Abstract
The Group IV viruses have a positive sense genome. Positive sense RNA can be translated directly into protein, without a DNA intermediate and without creating a complementary RNA strand. To replicate its genome, though, a complementary DNA strand is required. The positive RNA strand serves as a template for an RNA-dependent RNA polymerase, yielding a complementary RNA strand, to form a dimer with the template strand. The double-stranded RNA subsequently serves as the template for a new positive sense genome. The positive strand RNA genome is independently infectious, for most Group IV viruses. This means that in the absence of a capsid, envelope, or enclosed proteins, the RNA molecule, when inserted into a cell, is capable of using host cell machinery to construct additional viruses. There are six subclasses of the Group IV single-stranded positive-sense RNA viruses: Picornaviridae, Togaviridae, Coronaviridae, Hepeviridae, Caliciviridae, Flaviviridae, and Astroviridae. As expected, within each class, viruses share structural similarities; but there are no properties, other than the defining property of a (+)-sense single stranded RNA genome, that extends to all six classes of the Group IV viruses. For example, some classes have envelopes (i.e., Flaviviridae, Togaviridae, Coronaviridae), and others do not (i.e., Caliciviridae, Picornaviridae, Hepeviridae, and Astroviridae).
Keywords
West nile fever, Yellow fever, Dengue fever, Epidemic polyarthritis, Sindbis fever, Western equine encephalomyelitis, German measles, Hepatitis
“Simplicity is the ultimate sophistication.”
Leonardo da Vinci
Group I, dsDNA (Chapter 39)
Group II, ssDNA (Chapter 40)
Group III, dsRNA (Chapter 41)
- Group IV (+)ssRNA (Chapter 42)
- Nidovirales
- Coronaviridae
- *SARS virus
- *Torovirus species
- Hepeviridae:
- *Hepatitis E
- Caliciviridae
- *Norovirus, formerly Norwalk virus
- *Sapporo virus
- Togaviridae
- Alphavirus viral diseases
- *Chikungunya
- *Eastern equine encephalomyelitis virus
- *Getah virus
- *Mayaro virus
- *Mucambo virus
- *O’nyong’nyong virus
- *Ross river virus
- *Barmah forest virus
- *Sagiyama virus
- *Semliki forest virus
- *Sindbis virus
- *Tonate virus
- *Venezuelan equine encephalomyelitis virus
- *Western equine encephalomyelitis virus
- Rubivirus
- *Rubella virus
- Flaviviridae
- Hepacivirus
- *Hepatitis C
- Flavivirus
- *Dengue virus types 1–4
- *Hepatitis G virus
- *Japanese B encephalitis virus
- *Murray Valley encephalitis virus
- *Rocio virus
- *Spondweni virus
- *St Louis encephalitis
- *Wesselsbron
- *West Nile virus (West Nile fever)
- *Yellow fever virus (yellow fever)
- Tick-borne virus group
- *Absettarov
- *Hanzalova
- *Hypr
- *Kumlinge
- *Kyasanur forest disease
- *Louping ill (tick-borne encephalitis)
- *Negishi
- *Omsk
- *Powassan (tick-borne encephalitis)
- *Langat (tick-borne encephalitis)
- *Russian spring summer encephalitis
- Hepatitis G virus group
- *Hepatitis G virus
- Picornaviridae
- Enterovirus
- *Coxsackievirus
- *Echovirus
- *Poliovirus
- *Enterovirus 68–109
- *Rhinovirus A and B
- Hepatovirus
- *Hepatitis A, alternately human enterovirus type 72
- Astroviridae
- *Astrovirus species
Group V (–)ssRNA (Chapter 43)
Group VI, ssRNA-RT (Chapter 44)
Group VII, dsDNA-RT (Chapter 45)
Prions (Chapter 46)
The Group IV viruses have a positive sense RNA genome. Positive sense RNA can be translated directly into protein, without a DNA intermediate and without creating a complementary RNA strand. To replicate its genome, though, a complementary RNA strand is required. The positive RNA strand serves as a template for an RNA-dependent RNA polymerase, yielding a complementary RNA strand, to form a dimer with the template strand. The double-stranded RNA subsequently serves as the template for a new positive sense genome.
The positive strand RNA genome is independently infectious, for most Group IV viruses. This means that in the absence of a capsid, envelope, or enclosed proteins, the RNA molecule, when inserted into a cell, is capable of using host cell machinery to construct additional viruses. Such viruses can be extremely small. In an experiment conducted in the late 1960s, Sol Spiegelman and his coworkers developed a method by which smaller and smaller viral RNA molecules could be isolated that were capable of replicating if provided with a specific RNA-dependent RNA polymerase and substrate nucleotides. A minimalist infectious viral genome was eventually selected that was only 220 nucleotides (bases) in length [133].
As discussed in the overview (Chapter 38), we know very little about the phylogenetic relationship among viruses. Consequently, we subclassify the Group IV viruses based on structural similarities: symmetry of capsid, presence of absence of a viral envelope, size. There are six subclasses of the Group IV single-stranded positive-sense RNA viruses: Picornaviridae, Togaviridae, Coronaviridae, Hepeviridae, Caliciviridae, Flaviviridae, and Astroviridae. As expected, within each class, viruses share structural similarities; but there are no properties, other than the defining property of a (+)sense single-stranded RNA genome, that extends to all six classes of the Group IV viruses. For example, some classes have envelopes (i.e. Flaviviridae, Togaviridae, Coronaviridae), and others do not (i.e. Caliciviridae, Picornaviridae, Hepeviridae, and Astroviridae).
- Group IV (+)ssRNA
- Nidovirales
- Coronaviridae
- *SARS virus
- Torovirinae
- *Human torovirus
Members of Class Nidovirales do not package polymerase in the viral particle. The genome is read directly using host enzymes. Class Nidovirales contains one subclass with viruses that infect humans: Class Coronaviridae. The coronaviruses are characterized by glycoprotein spikes (peplomers) that protrude from the envelope that encloses the round nucleocapsid. The arrangement of peplomers resembles a corona (hence, coronavirus).
SARS (severe acute respiratory syndrome) virus produces a flu-like illness, and is spread by close human contact. The earliest outbreak of SARS occurred in Southeast Asia, in 2002. Soon thereafter, cases occurred in distant locations, including Toronto, Canada and Bangalore, India. The worldwide response to SARS was possibly the most intensive public health effort ever launched to stem an epidemic of a new, and potentially fatal, viral disease. By 2004, China, the epicenter of the fledgling epidemic, was declared SARS-free.
Toroviruses infect a variety of mammals. Human torovirus is a rare cause of enteritis.
- Group IV (+)ssRNA
- Hepeviridae
- *Hepatitis E
Class Hepeviridae is a tentative class, with just one genus and one species, the hepatitis E virus. It is possible that the hepatitis E virus will be re-assigned to an existing subclass of Group IV or will be assigned to a newly named subclass. Hepatitis E is spread from human to human by a fecal–oral route or by food contaminated with feces of infected mammals. The resulting hepatitis has a clinical course similar to that seen with Hepatitis A (i.e., self-limited disease, not leading to cirrhosis). Pregnant women infected with Hepatitis E are at increased risk for developing fulminant hepatitis, which may be fatal.
Hepevirus should not be confused with the orthographically similar “herpesvirus”. Also, readers should not confuse Class Hepeviridae (Hepatitis E virus) with Class Hepacivirus, a subclass of Class Flaviviridae that contains the Hepatitis C virus. Neither of these Group IV subclasses should be confused with Class Hepadnaviridae (Group VII, Chapter 45).
- Group IV (+)ssRNA
- Caliciviridae
- *Norovirus, formerly Norwalk virus
- *Sapporo virus
Class Caliciviridae contains small non-enveloped viruses, 35–40 nm in diameter, just a tad larger than members of Class Picornaviridae. They take their name from the Latin root, calyx, meaning goblet, referring to the cup-shaped capsid depressions. Members of Class Caliciviridae cause acute gastroenteritis in humans.
- Group IV (+)ssRNA
- Togaviridae
- Alphavirus diseases
- *Chikungunya
- *Eastern equine encephalomyelitis virus
- *Getah virus
- *Mayaro virus
- *Mucambo virus
- *O’nyong’nyong virus
- *Ross river virus
- *Barmah forest virus
- *Sagiyama virus
- *Semliki forest virus
- *Sindbis virus
- *Tonate virus
- *Venezuelan equine encephalomyelitis virus
- *Western equine encephalomyelitis virus
- Rubivirus
- *Rubella virus
Class Togaviridae is named for its distinctive coat (the “toga”). Togaviruses have a genome approximately 12 000 kilobases in length, somewhat larger than the genome of Class Picornaviridae. Togaviruses live in the cytoplasm of their host cells, where viral replication and gene expression take place. Class Togaviridae contains two subclasses: Class Alphavirus and Class Rubivirus. All the members of Class Alphavirus are arboviruses (arthropod-borne viruses) spread by mosquitoes (primarily) or ticks. Class Rubivirus contains only one species that is infective in humans: Rubella virus, the cause of German measles. Rubella is spread directly from person to person, without an insect vector. Readers should not confuse Rubella virus with the measles virus, Rubeola. Rubeola virus is a paramyxovirus (Group V, Chapter 43), unrelated to Rubella virus.
A few of the alphaviruses typify the group. Chikungunya is a disease that produces a clinical syndrome similar to that seen with Dengue virus (Class Flaviviridae), Ross river virus and Barmah forest virus; namely, an acute febrile phase followed by a prolonged arthralgic phase. Chikungunya fever is spread by the Aedes mosquito, and the reservoir is primarily human (i.e. transmission is human to mosquito to human). In recent years, the incidence of Chikungunya has recently increased in Asia and Africa and is now an emerging disease in Europe [76].
Ross river virus and Barmah forest virus produce clinically and geographically indistinguishable diseases, sometimes referred to collectively as epidemic polyarthritis. The diseases are spread by various species of mosquito, and both are endemic to Australasia. They produce an acute influenza-like illness, followed by arthralgia. Joint pains may persist for many months. The reservoir for both viruses seem to be, primarily, marsupials.
- Group IV (+)ssRNA
- Flaviviridae
- Hepacivirus
- *Hepatitis C
- Flavivirus
- *Dengue virus types 1–4
- *Japanese B encephalitis virus
- *Murray Valley encephalitis virus
- *Rocio virus
- *Spondweni virus
- *St Louis encephalitis
- *Wesselsbron
- *West Nile virus
- *Yellow fever virus
- Tick-borne virus group
- *Absettarov virus
- *Hanzalova virus
- *Hypr virus
- *Kumlinge virus
- *Kyasanur forest disease virus
- *Louping ill (tick-borne encephalitis)
- *Negishi virus
- *Omsk virus
- *Powassan (tick-borne encephalitis)
- *Langat (tick-borne encephalitis)
- *Russian spring summer encephalitis
- Hepatitis G virus group
- *Hepatitis G virus
The members of Class Flaviviridae are enveloped, spherical, and have a diameter of about 50 nm. Most members of Class Flaviviridae are arthropod-borne, being transmitted by a tick (Class Chelicerata, Chapter 29) or a mosquito (Class Hexapoda, Chapter 30). The subclasses of Class Flaviviridae that contain infectious viruses in humans are: Hepacivirus, Flavivirus, tick-borne virus group, and hepatitis G virus group.
Hepatitis C virus is the only member of Class Hepacivirus. Hepatitis C is a common cause of hepatitis and chronic liver disease. It is spread from person to person by sexual transmission or by contact with infected blood, or blood products, and can be spread by contaminated needles. It can be transmitted to infants born to infected mothers. People who develop hepatitis from this virus often develop chronic infection of the liver, that varies from person to person in intensity and in the likelihood of progressing to cirrhosis. Over one percent of the USA population is infected with hepatitis C.
Class Flavivirus (from the Latin “flavus,” meaning yellow), is a subclass of Class Flaviviridae, both named for the yellow (jaundiced) skin resulting from infection with its most notorious species, Yellow fever virus. The flaviviruses includes some of the most common and deadly viruses on earth, led by yellow fever virus and Dengue fever virus. Among the flaviviruses are numerous encephalitis-producing viruses, that have specific geographic distributions: Japanese encephalitis virus (mosquito-borne), Murray Valley encephalitis virus (mosquito-borne), St. Louis encephalitis virus (mosquito-borne), West Nile encephalitis virus (mosquito-borne), and a host of viruses collectively known as tick-borne encephalitis viruses.
Yellow fever virus seems to have originated in Africa and spread to other continents in the mid-seventeenth century. It is responsible for hundreds of thousands of deaths in North America alone. The disease is carried by primates, including humans, and transmitted from person to person by the bite of a mosquito (Aedes aegypti). It produces hepatitis and hemorrhaging (hence, it is included among the hepatitis viruses and the hemorrhagic fever viruses).
Yellow fever virus is associated with an impressive number of medical breakthroughs, being the first disease demonstrated to be transmitted by an arthropod, among the first disease shown to be caused by a virus, and among the first infections controlled by a live vaccine. Effective methods of yellow fever prevention, through the eradication of the Aedes aegypti were developed in the 1890s, and an effective vaccine was developed in the 1930s. Today, there are about 200 000 cases of yellow fever, worldwide, with about 30 000 deaths [134]. Most infections occur in Africa.
While the incidence of yellow fever has diminished over the past century, the incidence of dengue fever is increasing. Dengue, like yellow fever, is transmitted primarily by the Aedes aegypti mosquito. More than 50 million dengue virus infections occur each year, worldwide. Most infections are asymptomatic or cause only mild disease, but a minority of infections are severe and may cause death. Typical cases exhibit fever and intense pain in muscles and joints (hence the alternate name of the disease, breakbone fever). Fevers can come and go. Capillary permeability is a common feature of the disease, and this may result in petechiae, the egress of fluid from the vascular compartment, shock (so-called Dengue shock syndrome), and hemorrhage (hemorrhagic syndrome). Severe cases of dengue, if untreated, may have a fatality rate approaching 20%. Like yellow fever, dengue is included in the group of hemorrhagic viruses.
The hepatitis G virus group, in Class Flaviviridae, contains only one species, hepatitis G virus, which had been traditionally included among the named hepatitis viruses. Hepatitis G is now considered to be an “orphan virus” (i.e., a virus that has no associated disease). The hepatitis G virus is found in a small percentage of donated blood units.
- Group IV (+)ssRNA
- Picornaviridae
- Enterovirus
- *Coxsackievirus
- *Echovirus
- *Poliovirus
- *Enterovirus 68–109
- *Rhinovirus A and B
- Hepatovirus
- *Hepatitis A, alternately human enterovirus type 72
Members of Class Picornaviridae have a small RNA genome, as small as 7 kilobases (i.e., 7000 nucleotides) in length. The picornaviruses include two subclasses: Enterovirus and Hepatovirus.
Members of Class Enterovirus are among the most prevalent human pathogens. In active infections, the virus can often be recovered from feces and respiratory secretions. Poliovirus, spread by contaminated fecal material, produces a paralytic syndrome characterized by inflammation and destruction of the anterior horn cells of the spinal cord. Many poliovirus infections do not result in disease, but disease-free infected individuals are carriers, transiently producing infective virus. Aside from poliovirus, other enteroviruses may display neurotropism, producing aseptic meningitis and flacid paralysis [135].
There are a huge number of serotypes in Class Enterovirus, spread among the Coxsackievirus, Echovirus, and Enterovirus viruses. They produce non-specific flu-like illnesses, and various strains produce distinctive syndromes such as hand-foot-mouth disease, herpangina, and hemorrhagic conjunctivitis, and Bornholm disease (epidemic pleurodynia). Enterovirus infections are common pediatric maladies. Infections in newborns can be severe, with hepatitis, encephalitis, and sepsis.
Class Enterovirus also includes the rhinoviruses, which contains more than 100 variant strains. The rhinoviruses account for most instances of the common cold.
Class Hepatovirus contains hepatitis A, a cause of hepatitis. As you would expect from a member of Class Enterovirus, hepatitis A is typically spread by the fecal–oral route. The resulting hepatitis is acute, and generally subsides without sequelae. Unlike hepatitis B and C, hepatitis A does not progress to chronic hepatitis and cirrhosis.
- Group IV (+)ssRNA
- Astroviridae
- *Astrovirus species
Members of Class Astroviridae, like those of Class Picornaviridae and Class Caliciviridae, lack an envelope. The class contains one species that is pathogenic in humans: Astrovirus. Astrovirus causes enteritis. Infections are especially common in children, accounting for more than 5% of enteritis cases in the pediatric age group.
Infectious species:
- Enterovirus
- Coxsackievirus (flu-like illness, hand-food-mouth disease, herpangina, hemorrhagic conjunctivitis, aseptic meningitis; in newborns, myocarditis, meningoencephalitis, hepatitis)
- Echovirus, Enteric Cytopathic Human Orphan virus (flu-like illness, aseptic meningitis; in newborns, severe myocarditis hepatitis, and systemic infection)
- Poliovirus (polio)
- Enterovirus 68–109 (flu-like illnesses and other syndromes associated with Coxsackievirus and Echovirus)
- Rhinovirus (common cold)
- Hepatovirus
- Hepatitis A (hepatitis A)
- Alphavirus viral diseases
- Chikungunya virus, a member of Semliki Forest virus complex (Chikungunya fever, rash, arthritis)
- Eastern equine encephalomyelitis virus (encephalitis)
- Getah virus (asymptomatic in humans)
- Mayaro virus, a member of Semliki Forest virus complex (rash, arthritis)
- Mucambo virus (encephalitis)
- O’nyong’nyong virus, a member of Semliki Forest virus complex (rash, arthritis)
- Ross river virus, a member of Semliki Forest virus complex (epidemic polyarthritis)
- Barmah forest virus (epidemic polyarthritis)
- Sagiyama virus, a subtype of Ross River virus (asymptomatic in humans)
- Semliki forest virus, a member of Semliki Forest virus complex (rash, arthritis)
- Sindbis virus (Sindbis fever, rash, arthritis)
- Tonate virus (encephalitis)
- Venezuelan equine encephalomyelitis virus (encephalitis, often causing, in humans, a flu-like illness with high fever and headache)
- Western equine encephalomyelitis virus (Western equine encephalomyelitis)
- Rubivirus
- Rubella virus (German measles)
- Coronaviridae
- SARS virus (severe acute respiratory syndrome)
- Torovirus species (gastroenteritis)
- Hepeviridae
- Hepatitis E (hepatitis)
- Caliciviridae
- Norovirus, formerly Norwalk virus (epidemic gastroenteritis)
- Sapporo virus (mild gastroenteritis in children)
Flaviviridae
- Hepacivirus
- Hepatitis C (hepatitis C)
- Flavivirus
- Dengue virus types 1–4 (dengue fever; severe form is called dengue hemorrhagic fever)
- Japanese B encephalitis virus (encephalitis, with less than 1% of human infections leading to disease)
- Murray Valley encephalitis virus (Murray Valley encephalitis, formerly known as Australian encephalitis)
- Rocio virus (meningoencephalitis)
- Spondweni virus (acute febrile illness)
- St Louis encephalitis (encephalitis)
- Wesselsbron virus (fever, flu-like illness, most infections are subclinical)
- West Nile virus (West Nile fever). Aedes albopictus is a vector for West Nile
- Yellow fever virus (yellow fever). The yellow fever mosquito is Aedes aegypti
- Tick-borne virus group
- Absettarov virus (encephalitis)
- Hanzalova virus (encephalitis)
- Hypr virus (encephalitis)
- Kumlinge virus (fever and encephalitis)
- Kyasanur forest disease virus (hemorrhagic fever)
- Louping ill virus (tick-borne encephalitis)
- Negishi virus (encephalitis)
- Omsk virus (hemorrhagic fever)
- Powassan virus (tick-borne encephalitis)
- Langat virus (tick-borne encephalitis)
- Russian spring summer encephalitis virus (encephalitis)
- Hepatitis G virus group
- Hepatitis G virus, alternately GB virus CF (“orphan virus” not associated with any human disease)
- Astroviridae
- Astrovirus species (gastroenteritis)