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INFLUENZA VIRUSES
Influenza viruses are the only members of the orthomyxovirus family. The orthomyxoviruses differ from the paramyxoviruses primarily in that the former have a segmented RNA genome (usually eight pieces), whereas the RNA genome of the latter consists of a single piece.1The term "myxo" refers to the observation that these viruses interact with mucins (glycoproteins on the surface of cells).
In addition, the orthomyxoviruses are smaller (110 nm in diameter) than the paramyxoviruses (150 nm in diameter). See Table 39–1 for additional differences.
Table 39–1. Properties of Orthomyxoviruses and Paramyxoviruses.Property
/ Orthomyxoviruses
/ Paramyxoviruses
/
Viruses / Influenza A, B, and C viruses / Measles, mumps, respiratory syncytial, and parainfluenza viruses
Genome / Segmented (eight pieces) single-stranded RNA of negative polarity / Nonsegmented single-stranded RNA of negative polarity
Virion RNA polymerase / Yes / Yes
Capsid / Helical / Helical
Envelope / Yes / Yes
Size / Smaller (110 nm) / Larger (150 nm)
Surface spikes / Hemagglutinin and neuraminidase on different spikes / Hemagglutinin and neuraminidase on the same spike1
Giant cell formation / No / Yes
1Individual viruses differ in detail. See Table 39–4.
Table 39–2 shows a comparison of influenza A virus with several other viruses that infect the respiratory tract. Table 39–3 describes some of the important clinical features of influenza virus and compares them with the clinical features of the other medically important viruses in this chapter.
Table 39–2. Features of Viruses that Infect the Respiratory Tract.1Virus
/ Disease
/ Number of Serotypes
/ Lifelong Immunity to Disease
/ Vaccine Available
/ Viral Latency
/ Treatment
/
RNA viruses
Influenza virus / Influenza / Many / No / + / – / Amantadine rimantidine, oseltamivir, zanamivir
Parainfluenza virus / Croup / Many / No / – / – / None
Respiratory syncytial virus / Bronchiolitis / One / Incomplete / – / – / Ribavirin
Rubella virus / Rubella / One / Yes / + / – / None
Measles virus / Measles / One / Yes / + / – / None
Mumps virus / Parotitis, meningitis / One / Yes / + / – / None
Rhinovirus / Common cold / Many / No / – / – / None
Coronavirus / Common cold, SARS2 / Three / No / – / – / None
Coxsackievirus / Herpangina, pleurodynia, myocarditis / Many / No / – / – / None
DNA viruses
Herpes simplex virus type 1 / Gingivostomatitis / One / No / – / + / Acyclovir in immunodeficient patients
Epstein-Barr virus / Infectious mononucleosis / One / Yes / – / + / None
Varicella-zoster virus / Chickenpox, shingles / One / Yes3 / – / + / Acyclovir in immunodeficient patients
Adenovirus / Pharyngitis, pneumonia / Many / No / +4 / + / None
1Influenza virus, parainfluenza virus, respiratory syncytial virus, rubella virus, measles virus, mumps virus, and coronavirus are enveloped RNA viruses and are described in this chapter.
2SARS is severe acute respiratory syndrome.
3Lifelong immunity to varicella (chickenpox) but not to zoster (shingles).
4For military recruits only.
Table 39–3. Clinical Features of Certain RNA Enveloped Viruses.
Virus
/ Rash Occurs
/ Giant Cells Formed
/ Type of Vaccine
/ Immune Globulins Commonly Used
/
Influenza / No / No / Killed / No
Respiratory syncytial / No / Yes / None / No
Measles / Yes / Yes / Live / No
Rubella / Yes / No / Live / No
Rabies / No / No / Killed / Yes
Disease
Influenza A virus causes worldwide epidemics (pandemics) of influenza; influenza B virus causes major outbreaks of influenza; and influenza C virus causes mild respiratory tract infections but does not cause outbreaks of influenza. The pandemics caused by influenza A virus occur infrequently (the last one was in 1968), but major outbreaks caused by this virus occur virtually every year in various countries. Each year, influenza is the most common cause of respiratory tract infections that result in physician visits and hospitalizations.
In the 1918 influenza pandemic, more Americans died than in World War I, World War II, the Korean war, and the Vietnam war combined. Influenza B virus does not cause pandemics, and the major outbreaks caused by this virus do not occur as often as those caused by influenza A virus. It is estimated that approximately 36,000 people die of influenza each year in the United States.
Important Properties
Influenza virus is composed of asegmentedsingle-stranded RNA genome, a helical nucleocapsid, and an outer lipoprotein envelope (see Color Plate 27). The virion contains an RNA-dependentRNA polymerase,which transcribes thenegative-polaritygenome into mRNA. The genome is therefore not infectious.
Color Plate 27
Influenza virus—Electron micrograph. Long arrow points to the helical nucleocapsid of influenza virus. The nucleocapsid contains the segmented, negative polarity genome RNA. Short arrow points to the spikes on the virion envelope. The spikes are the hemagglutinin and neuraminidase proteins. Provider: CDC/Dr. Erskine Palmer and Dr. M. Martin.
The envelope is covered with two different types of spikes, ahemagglutininand aneuraminidase.2Influenza A virus has 16 antigenically distinct types of hemagglutinin (HA) and 9 antigenically distinct types of neuraminidase (NA). As discussed below, some of these types cause disease in humans, but most of the types typically cause disease in other animal species such as birds, horses, and pigs.
The function of the hemagglutinin is to bind to the cell surface receptor (neuraminic acid, sialic acid) to initiate infection. In the clinical laboratory, the hemagglutinin agglutinates red blood cells, which is the basis of a diagnostic test called the hemagglutination inhibition test. The hemagglutinin is also the target of neutralizing antibody.
The neuraminidase cleaves neuraminic acid (sialic acid) to release progeny virus from the infected cell. The hemagglutinin functions at the beginning of infection, whereas the neuraminidase functions at the end. Neuraminidase also degrades the protective layer of mucus in the respiratory tract. This enhances the ability of the virus to infect the respiratory epithelium.
Influenza viruses, especially influenza A virus, showchanges in the antigenicityof their hemagglutinin and neuraminidase proteins; this property contributes to their capacity to cause devastatingworldwide epidemics.There are two types of antigenic changes: (1)antigenic shifts,which are major changes based on the reassortment of segments of the genome RNA and (2)antigenic drifts,which are minor changes based on mutations in the genome RNA. Note that in reassortment, entire segments of RNA are exchanged, each one of which codes for a single protein, e.g., the hemagglutinin (Figure 39–1).
Figure 39–1.
Antigenic shift in influenza virus. A human strain of influenza virus containing the gene encoding one antigenic type of hemagglutinin (colored blue) infects the same lung cell as a chicken strain of influenza virus containing the gene encoding a different antigenic type of hemagglutinin (colored black). Reassortment of the genome RNA segments that encode the hemagglutinin occurs, and a new strain of influenza virus is produced containing the chicken type of hemagglutinin (colored black).
Influenza viruses have two matrix proteins: The M1 matrix protein resides between the internal nucleoprotein segments and the envelope and provides structural integrity. TheM2 matrix protein forms an ion channelbetween the interior of the virus and the external milieu. This ion channel plays an essential role in theuncoating of the virionafter it enters the cell. It transports protons into the virion causing the disruption of the envelope, which allows the nucleocapsid containing the genome RNA to migrate to the nucleus.
Influenza viruses have bothgroup-specificandtype-specificantigens.
1. The internal ribonucleoprotein is the group-specific antigen that distinguishes influenza A, B, and C viruses.
2. The hemagglutinin and the neuraminidase are the type-specific antigens located on the surface. Antibody against the hemagglutinin neutralizes the infectivity of the virus (and prevents disease), whereas antibody against the group-specific antigen (which is located internally) does not. Antibody against the neuraminidase does not neutralize infectivity but does reduce disease, perhaps by decreasing the amount of virus released from the infected cell and thus reducing spread.
An important determinant of the virulence of this virus is a nonstructural protein called NS 1 encoded by the genome RNA of influenza virus. NS 1 has several functions, but the one pertinent to virulence is its ability to inhibit the production of interferon mRNA. As a result, innate defenses are reduced and viral virulence is correspondingly enhanced.
Many species of animals (e.g., aquatic birds, chickens, swine, and horses) have their own influenza A viruses. Theseanimal viruses are the source of the RNA segmentsthat encode the antigenic shift variants that cause epidemics among humans. For example, if an avian and a human influenza A virus infect the same cell (e.g., in a farmer's respiratory tract), reassortment could occur and a new variant of the human A virus, bearing the avian virus hemagglutinin, may appear.
There is evidence that aquatic birds (waterfowl) are a common source of these new genes and that the reassortment event leading to new human strains occurs in pigs. There are 16 types of HA (H1 to H16) and 9 types of NA (N1 to N9) found in waterfowl. In humans, three types of HA (H1, H2, and H3) and two types of NA (N1 and N2) predominate.
Because influenza B virus is only a human virus, there is no animal source of new RNA segments. Influenza B virus therefore does not undergo antigenic shifts. It does, however, undergo enough antigenic drift that the current strain must be included in the new version of the influenza vaccine produced each year. Influenza B virus has no antigens in common with influenza A virus.
A/Philippines/82 (H3N2) illustrates the nomenclature of influenza viruses. "A" refers to the group antigen. Next are the location and year the virus was isolated. H3N2 is the designation of the hemagglutinin (H) and neuraminidase (N) types. The H1N1 and H3N2 strains of influenza A virus are the most common at this time and are the strains included in the current vaccine. The H2N2 strain caused a pandemic in 1968.
In 1997, the H5N1 strain that causesavian influenza,primarily in chickens, caused an aggressive form of human influenza with high mortality in Hong Kong. In the winter of 2003–2004, an outbreak of avian influenza caused by H5N1 strain killed thousands of chickens in several Asian countries. Millions of chickens were killed in an effort to stop the spread of the disease. The number of human cases of H5N1 influenza between 2003 and February 2008 is 359 of whom 226 died, a mortality rate of 63%. Note that these 359 people were infected directly from chickens. Both the respiratory secretions and the chicken guano contain infectious virus. The spread of the H5N1 strain from person to person occurs rarely but remains a major concern because it could increase dramatically if reassortment with the human-adapted strains occurs. In 2005, the H5N1 virus spread from Asia to Siberia and into eastern Europe, where it killed thousands of birds but has not caused human disease.
As of this writing (January 2008), there have been no cases of human influenza caused by an H5N1 virus in the United States. However, there have been two cases of human influenza caused by an H7N2 strain of avian influenza virus. In 2005, the RNA of the virus that caused the 1918 pandemic was sequenced and found to resemble avian influenza strains.
The ability of the H5N1 strain to infect chickens (and other birds) more effectively than humans is due to the presence of a certain type of viral receptor throughout the mucosa of the chicken respiratory tract. In contrast, humans have this type of receptor only in the alveoli, not in the upper respiratory tract. This explains why humans are rarely infected with the H5N1 strain. However, when the exposure is intense, the virus is able to reach the alveoli and causes severe pneumonia.
The virulence of the H5N1 strain is significantly greater than the H1N1 and H3N2 strains that have been causing disease in humans for many years. This is attributed to two features of the H5N1 strain, namely, relative resistance to interferon and increased induction of cytokines, especially TNF. The increase in cytokines is thought to mediate the pathogenesis of the pneumonia and acute respiratory distress syndrome (ARDS) seen in H5N1 infection.
The H5N1 strain is sensitive to the neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza) but not to amantadine and rimantidine, the drugs that inhibit entry (see Treatment section below). Tamiflu is the drug of choice for both treatment and prevention. There is no human vaccine against the H5N1 strain, but there is one available for use in avian species.
Summary of Replicative Cycle
The virus adsorbs to the cell when the viral hemagglutinin interacts with sialic acid receptors on the cell surface. (The hemagglutinin on the virion surface is cleaved by extracellular proteases to generate a modified hemagglutinin that actually mediates attachment to the cell surface.) The virus then enters the cell in vesicles and uncoats within an endosome. Uncoating is facilitated by the low pH within the endosome. Protons pass through the ion channel formed by the M2 protein into the interior of the virion. This disrupts the virion envelope and frees the nucleocapsid to enter the cytoplasm and then migrate to the nucleus where the genome RNA is transcribed.