Influenzavirus A

Influenzavirus A
Influenzavirus B
Influenzavirus C
Isavirus
Thogotovirus

Influenzavirus A is a genus of a family of viruses called Orthomyxoviridae in virus classification. Influenzavirus A has only one species in it; that species is called "Influenza A virus". Influenza A virus causes "avian influenza" (also known as bird flu, avian flu, Influenzavirus A flu, type A flu, or genus A flu). It is hosted by birds, but may infect several species of mammals. All known subtypes are endemic in birds. WHO Avian influenza (" bird flu") - Fact sheet

Variants and subtypes

Variants of this species are sometimes named according to the species the strain is endemic in or adapted to. The main variants named using this convention are:

Avian variants have also sometimes been named according to their deadliness in poultry, especially chickens:

Low Pathogenic Avian Influenza (LPAI)
Highly Pathogenic Avian Influenza (HPAI), also called: deadly flu or death flu

The Influenza A virus subtypes are labeled according to an H number (for hemagglutinin) and an N number (for neuraminidase). Each subtype virus has mutated into a variety of strains with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species. Most known strains are extinct strains. For example, the annual flu subtype H3N2 no longer contains the strain that caused the Hong Kong Flu.

Influenza A viruses are negative sense, single-stranded, segmented RNA viruses. "There are 16 different HA antigens (H1 to H16) and nine different NA antigens (N1 to N9) for influenza A. Until recently, 15 HA types had been recognized, but a new type (H16) was isolated from black-headed gulls caught in Sweden and the Netherlands in 1999 and reported in the literature in 2005." CIDRAP - Center for Infectious Disease Research And Policy Pandemic Influenza Overview

Annual flu

The annual flu (also called "seasonal flu" or "human flu") in the U.S. "results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S." whitehouse.gov National Strategy for Pandemic Influenza - Introduction - "Although remarkable advances have been made in science and medicine during the past century, we are constantly reminded that we live in a universe of microbes - viruses, bacteria, protozoa and fungi that are forever changing and adapting themselves to the human host and the defenses that humans create. Influenza viruses are notable for their resilience and adaptability. While science has been able to develop highly effective vaccines and treatments for many infectious diseases that threaten public health, acquiring these tools is an ongoing challenge with the influenza virus. Changes in the genetic makeup of the virus require us to develop new vaccines on an annual basis and forecast which strains are likely to predominate. As a result, and despite annual vaccinations, the U.S. faces a burden of influenza that results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S. A pandemic, or worldwide outbreak of a new influenza virus, could dwarf this impact by overwhelming our health and medical capabilities, potentially resulting in hundreds of thousands of deaths, millions of hospitalizations, and hundreds of billions of dollars in direct and indirect costs. This Strategy will guide our preparedness and response activities to mitigate that impact.".

The annually updated trivalent flu vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses. CDC Centers for Disease Control and Prevention - Research Article - Influenza A (H3N2) Outbreak, Nepal - "The 2003–2004 influenza season was severe in terms of its impact on illness because of widespread circulation of antigenically distinct influenza A (H3N2) Fujian-like viruses. These viruses first appeared late during the 2002–2003 influenza season and continued to persist as the dominant circulating strain throughout the subsequent 2003–2004 influenza season, replacing the A/Panama/2007/99-like H3N2 viruses (1). Of the 172 H3N2 viruses genetically characterized by the Department of Defense in 2003–2004, only 1 isolate (from Thailand) belonged to the A/Panama-like lineage. In February 2003, the World Health Organization (WHO) changed the H3N2 component for the 2004–2005 influenza vaccine to afford protection against the widespread emergence of Fujian-like viruses (2). The annually updated trivalent vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B viruses."

The dominant strain in January 2006 is H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005.

"human H3N2 influenza viruses are now endemic in pigs in southern China and can reassort with avian H5N1 viruses in this intermediate host." [http://www.nap.edu/books/0309095042/html/126.html NAP Books National Academies Press - Books - "The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005)" - page 126 - "H5N1 virus is now endemic in poultry in Asia (Table 2-1) and has gained an entrenched ecological niche from which to present a long-term pandemic threat to humans. At present, these viruses are poorly transmitted from poultry to humans, and there is no conclusive evidence of human-to-human transmission. However, continued, extensive exposure of the human population to H5N1 viruses increases the likelihood that the viruses will acquire the necessary characteristics for efficient human-to-human transmission through genetic mutation or reassortment with a prevailing human influenza A virus. Furthermore, contemporary human H3N2 influenza viruses are now endemic in pigs in southern China (Peiris et al., 2001) and can reassort with avian H5N1 viruses in this 'intermediate host.' Therefore, it is imperative that outbreaks of H5N1 disease in poultry in Asia are rapidly and sustainably controlled. The seasonality of the disease in poultry, together with the control measures already implemented, are likely to reduce temporarily the frequency of H5N1 influenza outbreaks and the probability of human infection."

Genetics

The Influenza A virus genome is contained on eight single (non-paired) RNA strands that code for ten proteins. The segmented nature of the genome allows for the exchange of entire genes between different viral strains when they cohabitate the same cell. The eight RNA segments are:

HA encodes hemagglutinin (about 500 molecules of hemagglutinin are needed to make one virion) "The extent of infection into host organism is determined by HA. Influenza viruses bud from the apical surface of polarized epithelial cells (e.g. bronchial epithelial cells) into lumen of lungs and are therefore usually pneumotropic. The reason is that HA is cleaved by tryptase clara which is restricted to lungs. However HAs of H5 and H7 pantropic avian viruses subtypes can be cleaved by furin and subtilisin-type enzymes, allowing the virus to grow in other organs than lungs." UniProtKB/Swiss-Prot entry P09345 Complete sequence of a cDNA clone of the hemagglutinin gene of influenza A/Chicken/Scotland/59 (H5N1) virus: comparison with contemporary North American and European strains.
NA encodes neuraminidase (about 100 molecules of neuraminidase are needed to make one virion).
NP encodes nucleoprotein.
M encodes two matrix proteins (the M1 and the M2) by using different reading frames from the same RNA segment (about 3000 matrix protein molecules are needed to make one virion).
NS encodes two distinct non-structural proteins (NS1 and NEP) by using different reading frames from the same RNA segment.
PA encodes an RNA polymerase.
PB1 encodes an RNA polymerase and PB1-F2 protein (induces apoptosis) by using different reading frames from the same RNA segment.
PB2 encodes an RNA polymerase.

The genome segments have common terminal sequences, and the ends of the RNA strands are partially complementary, allowing them to bond to each other by hydrogen bonds. After transcription from negative-sense to positive-sense RNA the +RNA strands get the cellular 5' cap added by cap snatching, which involves the viral protein NS1 binding to the cellular pre-mRNAs. The cap is then cleaved from the cellular pre-mRNA using a second viral protein, PB2. The short oligo cap is then added to the influenza +RNA strands, allowing its processing as messenger RNA by ribosomes. The +RNA strands also serve for synthesis of -RNA strands for new virions.

The RNA synthesis and its assembly with the nucleoprotein takes place in the cell nucleus, the synthesis of proteins takes place in the cytoplasm. The assembled virion cores leave the nucleus and migrate towards the cell membrane, with patches of viral transmembrane proteins (hemagglutinin, neuraminidase and M2 proteins) and an underlying layer of the M1 protein, and bud through these patches, releasing finished enveloped viruses into the extracellular fluid.

In nonhumans

See H5N1 for the current epizootic (an epidemic in nonhumans) and panzootic (a disease affecting animals of many species especially over a wide area) of H5N1 influenza

Wild fowl act as natural asymptomatic carriers of Influenza A viruses. Prior to the current H5N1 epizootic, strains of Influenza A virus had been demonstrated to be transmitted from wild fowl to only birds, pigs, horses, seals, whales and humans; and only between humans and pigs and between humans and domestic fowl; and not other pathways such as domestic fowl to horse. NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 30

H5N1 has been shown to be also transmitted to tigers, leopards, and domestic cats who were fed uncooked domestic fowl (chickens) with the virus. H3N8 viruses from horses have crossed over and caused outbreaks in dogs. Laboratory mice have been successfully infected with a variety of avian flu genotypes. NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 82 - "Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice (Tumpey et al., 2004). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (Kash et al., 2004). These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation. Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s (Tumpey et al., 2004), further supporting data of Shope from the 1930s (Shope, 1936). Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment, suggesting that current vaccination strategies are adequate against a 1918-like virus (Tumpey et al., 2004)."

Influenza A viruses spread in the air and in manure and survives longer in cold weather. It can also be transmitted by contaminated feed, water, equipment and clothing; however, there is no evidence that the virus can survive in well-cooked meat. Symptoms in animals vary, but virulent strains can cause death within a few days.

"Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents". NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 285 - "As of October 2001, the potential for use of infectious agents, such as anthrax, as weapons has been firmly established. It has been suggested that attacks on a nation’s agriculture might be a preferred form of terrorism or economic disruption that would not have the attendant stigma of infecting and causing disease in humans. Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents, generally following foot and mouth disease virus and Newcastle disease virus at or near the top of the list. Rapid detection techniques for bioweapon agents are a critical need for the first-responder community, on a par with vaccine and antiviral development in preventing spread of disease."

Avian influenza viruses that the OIE and others test for in order to control poultry disease include: H5N1, H7N2, H1N7, H7N3, H13N6, H5N9, H11N6, H3N8, H9N2, H5N2, H4N8, H10N7, H2N2, H8N4, H14N5, H6N5, H12N5 and others.

Known outbreaks of highly pathogenic flu in poultry 1959-2003WHO Avian influenza A(H5N1)- update 31: Situation (poultry) in Asia: need for a long-term response, comparison with previous outbreaks - Known outbreaks of highly pathogenic flu in poultry 1959-2003.

{|class="wikitable" width=500 Year Area Affected Strain 1959 Scotland chicken H5N1 1963 England turkey H7N3 1966 Ontario (Canada) turkey H5N9 1976 Victoria (Australia) chicken H7N7 1979 Germany chicken H7N7 1979 England turkey H7N7 1983 Pennsylvania (USA)* chicken,turkey H5N2 1983 Ireland turkey H5N8 1985 Victoria (Australia) chicken H7N7 1991 England turkey H5N1 1992 Victoria (Australia) chicken H7N3 1994 Queensland (Australia) chicken H7N3 1994 Mexico* chicken H5N2 1994 Pakistan* chicken H7N3 1997 New South Wales (Australia) chicken H7N4 1997 Hong Kong (China)* chicken H5N1 1997 Italy chicken H5N2 1999 Italy* turkey H7N1 2002 Hong Kong (China) chicken H5N1 2002 Chile chicken H7N3 2003 Netherlands* chicken H7N7 *Outbreaks with significant spread to numerous farms, resulting in great economic losses. Most other outbreaks involved little or no spread from the initially infected farms.

1979: "More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7)." NCBI - NLM - NIH National Center for Biotechnology Information (part of) U.S. National Library of Medicine (part of) National Institutes of Health (part of) US Government - Science. 1982 Feb 26;215(4536):1129-31. - Mass mortality of harbor seals: pneumonia associated with influenza A virus. - "More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7). The virus has avian characteristics, replicates principally in mammals, and causes mild respiratory disease in experimentally infected seals. Concurrent infection with a previously undescribed mycoplasma or adverse environmental conditions may have triggered the epizootic. The similarities between this epizootic and other seal mortalities in the past suggest that these events may be linked by common biological and environmental factors."

1995: "birds can develop asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive surveillance is required to detect these “silent epidemics” in time to curtail them. In Mexico, for example, mass vaccination of chickens against epidemic H5N2 influenza in 1995 has had to continue in order to control a persistent and evolving virus (Lee et al., 2004)." [http://www.nap.edu/books/0309095042/html/15.html NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 15 - "Unlike most other affected countries, Indonesia also instituted mass vaccination of healthy domestic birds against H5N1, followed by routine vaccination (China has a similar policy; other Asian countries are considering it 2004j) (Soebandrio, 2004). This is a risky strategy, because vaccinated birds can develop asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive surveillance is required to detect these “silent epidemics” in time to curtail them. In Mexico, for example, mass vaccination of chickens against epidemic H5N2 influenza in 1995 has had to continue in order to control a persistent and evolving virus (Lee et al., 2004)."

1997: "Influenza A viruses normally seen in one species sometimes can cross over and cause illness in another species. For example, until 1997, only H1N1 viruses circulated widely in the U.S. pig population. However, in 1997, H3N2 viruses from humans were introduced into the pig population and caused widespread disease among pigs. Most recently, H3N8 viruses from horses have crossed over and caused outbreaks in dogs." CDC Centers for Disease Control and Prevention - Transmission of Influenza A Viruses Between Animals and People

2000: "In California, poultry producers kept their knowledge of a recent H6N2 avian influenza outbreak to themselves due to their fear of public rejection of poultry products; meanwhile, the disease spread across the western United States and has since become endemic." NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 27.

2003: In Netherlands H7N7 influenza virus infection broke out in poultry on several farms. BBC News Early bird flu warning for Dutch - 6 November 2005

2004: In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus. CDC detailed analysis Human Illness from Avian Influenza H7N3, British Columbia

2005: Tens of millions of birds died of H5N1 influenza and hundreds of millions of birds were culled to protect humans from H5N1. H5N1 is endemic in birds in southeast Asia and represents a long term pandemic threat.

2006: H5N1 spreads across the globe killing hundreds of millions of birds and over 100 people causing a significant H5N1 impact from both actual deaths and predicted possible deaths.

Swine flu

Swine flu (or "pig influenza") refers to varieties of Influenza A virus that affect swine. These include genotypes of H1N1, H1N2 and H3N2.

Horse flu

Horse flu (or "Equine influenza") refers to varieties of Influenza A virus that affect horses. Horse 'flu viruses were only isolated in 1956. There are two main types of virus called equine-1 (H7N7) which commonly affects horse heart muscle and equine-2 (H3N8) which is usually more severe.

Dog flu

Dog flu (or "canine influenza") refers to varieties of Influenza A virus that affect dogs. The equine influenza virus H3N8 was found to infect and kill greyhound race dogs that had died from a respiratory illness at a Florida racetrack in January 2004.

H3N8

H3N8 is now endemic in birds, horses and dogs.

Human influenza virus

"Human influenza virus" usually refers to those subtypes that spread widely among humans. H1N1, H1N2, and H3N2 are the only known Influenza A virus subtypes currently circulating among humans. CDC Key Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus

Genetic factors in distinguishing between "human flu viruses" and "avian flu viruses" include:

PB2: (RNA polymerase): Amino acid (or residue) position 627 in the PB2 protein encoded by the PB2 RNA gene. Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine.

HA: (hemagglutinin): Avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Swine influenza viruses have the ability to bind both types of sialic acid receptors.

Human flu symptoms usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be fatal. The severity of the infection will depend to a large part on the state of the infected person's immune system and if the victim has been exposed to the strain before, and is therefore partially immune.

Highly pathogenic H5N1 avian flu in a human is far worse, killing 50% of humans that catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms. New England Journal of Medicine Volume 352:686-691 - February 17, 2005 - Number 7 - Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma

The Influenza A virus subtypes that have been confirmed in humans, ordered by the number of known human deaths, are:

H1N1 caused "Spanish Flu"
H2N2 caused "Asian Flu"
H3N2 caused "Hong Kong Flu"
H5N1 is the current pandemic threat
H7N7 has unusual zoonotic potential
H1N2 is currently endemic in humans and pigs
H9N2, H7N2, H7N3, H10N7.

Influenza A virus is the only species in the virus family of Orthomyxoviridae. All known subtypes of Influenza A virus infect birds. Influenza A virus is subdivided into subtypes based on hemagglutinin (H) and neuraminidase (N) protein spikes from the central virus core. There are 16 H types, each with up to 9 N subtypes, yielding a potential for 144 different H and N combinations.

In addition, Influenza A viruses may fall into one of 2 pathotypes: low (LPAI) and high (HPAI) pathogenicity, based on their virulence in poultry populations. Strains of influenza virus A subtypes H5 and H7 are found in both low pathogenic or high pathogenic forms while all other subtypes only have low pathogenic strains.

H1N1

A variant of H1N1 was responsible for the Spanish flu pandemic that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919. NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 7. A different variant exists in pig populations. Controversy arose in October, 2005, after the H1N1 genome was published in the journal, Science. Many fear that this information could be used for bioterrorism.

"When he compared the 1918 virus with today's human flu viruses, Dr. Taubenberger noticed that it had alterations in just 25 to 30 of the virus's 4,400 amino acids. Those few changes turned a bird virus into a killer that could spread from person to person." New York Times Published: November 8, 2005 - Hazard in Hunt for New Flu: Looking for Bugs in All the Wrong Places

H2N2

The Asian Flu was a pandemic outbreak of H2N2 avian influenza that originated in China in 1957, spread worldwide that same year during which a flu vaccine was developed, lasted until 1958 and caused between one and four million deaths.

H3N2

H3N2 evolved from H2N2 by antigenic shift and caused the Hong Kong Flu pandemic of 1968 and 1969 that killed up to 750,000. Detailed chart of its evolution here at PDF called Ecology and Evolution of the Flu "An early-onset, severe form of influenza A H3N2 made headlines when it claimed the lives of several children in the United States in late 2003." NAP Books National Academies Press Books - The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) - page 115 - "There is particular pressure to recognize and heed the lessons of past influenza pandemics in the shadow of the worrisome 2003–2004 flu season. An early-onset, severe form of influenza A H3N2 made headlines when it claimed the lives of several children in the United States in late 2003. As a result, stronger than usual demand for annual flu inactivated vaccine outstripped the vaccine supply, of which 10 to 20 percent typically goes unused. Because statistics on pediatric flu deaths had not been collected previously, it is unknown if the 2003–2004 season witnessed a significant change in mortality patterns."

The dominant strain of annual flu in January 2006 is H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005. Reason New York Times This Season's Flu Virus Is Resistant to 2 Standard Drugs By Altman Published: January 15, 2006

H5N1

H5N1 is known for its highly pathogenic strain of Influenza A virus, that is the world's major pandemic threat.

H7N7

H7N7 has unusual zoonotic potential. In 2003 in Netherlands 89 people were confirmed to have H7N7 influenza virus infection following an outbreak in poultry on several farms. One death was recorded.

H1N2

H1N2 is currently endemic in both human and pig populations. The new H1N2 strain appears to have resulted from the reassortment of the genes of the currently circulating influenza H1N1 and H3N2 subtypes. The hemagglutinin protein of the H1N2 virus is similar to that of the currently circulating H1N1 viruses and the neuraminidase protein is similar to that of the current H3N2 viruses.

H9N2

Low pathogenic avian influenza A (H9N2) infection was confirmed in 1999, in China and Hong Kong in two children, and in 2003 in Hong Kong in one child. All three fully recovered. CDC Avian Influenza Infection in Humans

H7N2

One person in New York in 2003 and one person in Virginia in 2002 were found to have serologic evidence of infection with H7N2. Both fully recovered. CDC Avian Influenza Infection in Humans

H7N3

In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus. Two cases of humans with avian influenza have been confirmed in that region. "Symptoms included conjunctivitis and mild influenza-like illness." CDC detailed analysis Human Illness from Avian Influenza H7N3, British Columbia Both fully recovered.

H10N7

In 2004 in Egypt H10N7 is reported for the first time in humans. It caused illness in two infants in Egypt. One child’s father is a poultry merchant. niaid.nih.gov Timeline of Human Flu Pandemics

Sources

Emerging Infectious Diseases, Special Issue, January 2006 (>20 excellent articles)
"Reining in bird flu: Answer may lie with reverse engineering". (Nov. 6, 2005). New Sunday Times, p. F18.
"Three million Asians may die". (Nov. 5, 2005). New Straits Times, p. 28.
"Avian Influenza Factsheet". World Health Organization. Retrieved November 16th, 2005.

Variants and subtypes

Annual flu

Genetics

In nonhumans

Human influenza virus

See also

Sources

Further reading

Gourt Home::Gourt :: Influenzavirus A

Variants and subtypes

Annual flu

Genetics

In nonhumans

Human influenza virus

See also

Sources

Further reading