Influenza A virus


Influenza A virus causes influenza in birds and some mammals, and is the only species of the genus Alphainfluenzavirus of the virus family Orthomyxoviridae. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon. Some isolates of influenza A virus cause severe disease both in domestic poultry and, rarely, in humans. Occasionally, viruses are transmitted from wild aquatic birds to domestic poultry, and this may cause an outbreak or give rise to human influenza pandemics.
Influenza A viruses are negative-sense, single-stranded, segmented RNA viruses.
The several subtypes are labeled according to an H number and an N number. There are 18 different known H antigens and 11 different known N antigens. H17N10 was isolated from fruit bats in 2012. H18N11 was discovered in a Peruvian bat in 2013.
Each virus subtype has mutated into a variety of strains with differing pathogenic profiles; some are pathogenic to one species but not others, some are pathogenic to multiple species.
A filtered and purified influenza A vaccine for humans has been developed and many countries have stockpiled it to allow a quick administration to the population in the event of an avian influenza pandemic. Avian influenza is sometimes called avian flu, and colloquially, bird flu. In 2011, researchers reported the discovery of an antibody effective against all types of the influenza A virus.

Variants and subtypes

Influenza type A viruses are RNA viruses categorized into subtypes based on the type of two proteins on the surface of the viral envelope:
The hemagglutinin is central to the virus's recognizing and binding to target cells, and also to its then infecting the cell with its RNA. The neuraminidase, on the other hand, is critical for the subsequent release of the daughter virus particles created within the infected cell so they can spread to other cells.
Different influenza viruses encode for different hemagglutinin and neuraminidase proteins. For example, the H5N1 virus designates an influenza A subtype that has a type 5 hemagglutinin protein and a type 1 neuraminidase protein. There are 18 known types of hemagglutinin and 11 known types of neuraminidase, so, in theory, 198 different combinations of these proteins are possible.
Some variants are identified and named according to the isolate they resemble, thus are presumed to share lineage ; according to their typical host ; according to their subtype ; and according to their deadliness. So a flu from a virus similar to the isolate A/Fujian/411/2002 is called Fujian flu, human flu, and H3N2 flu.
Variants are sometimes named according to the species in which the strain is endemic or to which it is adapted. The main variants named using this convention are:
Variants have also sometimes been named according to their deadliness in poultry, especially chickens:
Most known strains are extinct strains. For example, the annual flu subtype H3N2 no longer contains the strain that caused the Hong Kong flu.

Annual flu

The annual flu in the US. "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." Globally the toll of influenza virus is estimated at 290,000–645,000 deaths annually, exceeding previous estimates.
The annually updated, trivalent influenza vaccine consists of hemagglutinin surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses.
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.
"Contemporary human H3N2 influenza viruses are now endemic in pigs in southern China and can reassort with avian H5N1 viruses in this intermediate host."

FI6 antibody

, an antibody that targets the hemagglutinin protein, was discovered in 2011. FI6 is the only known antibody effective against all 16 subtypes of the influenza A virus.

Structure and genetics

Influenza type A viruses are very similar in structure to influenza viruses types B, C, and D. The virus particle is 80–120 nanometers in diameter such that the smallest virions adopt an elliptical shape. The length of each particle varies considerably, owing to the fact that influenza is pleomorphic, and can be in excess of many tens of micrometers, producing filamentous virions. Confusion about the nature of influenza virus pleomorphy stems from the observation that lab adapted strains typically lose the ability to form filaments and that these lab adapted strains were the first to be visualized by electron microscopy. Despite these varied shapes, the virions of all influenza type A viruses are similar in composition. They are all made up of a viral envelope containing two main types of proteins, wrapped around a central core.
The two large proteins found on the outside of viral particles are hemagglutinin and neuraminidase. HA is a protein that mediates binding of the virion to target cells and entry of the viral genome into the target cell. NA is involved in release from the abundant non-productive attachment sites present in mucus as well as the release of progeny virions from infected cells. These proteins are usually the targets for antiviral drugs. Furthermore, they are also the antigen proteins to which a host's antibodies can bind and trigger an immune response. Influenza type A viruses are categorized into subtypes based on the type of these two proteins on the surface of the viral envelope. There are 16 subtypes of HA and 9 subtypes of NA known, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.
The central core of a virion contains the viral genome and other viral proteins that package and protect the genetic material. Unlike the genomes of most organisms which are made up of double-stranded DNA, many viral genomes are made up of a different, single-stranded nucleic acid called RNA. Unusually for a virus, though, the influenza type A virus genome is not a single piece of RNA; instead, it consists of segmented pieces of negative-sense RNA, each piece containing either one or two genes which code for a gene product. The term negative-sense RNA just implies that the RNA genome cannot be translated into protein directly; it must first be transcribed to positive-sense RNA before it can be translated into protein products. The segmented nature of the genome allows for the exchange of entire genes between different viral strains.
The entire Influenza A virus genome is 13,588 bases long and is contained on eight RNA segments that code for at least 10 but up to 14 proteins, depending on the strain. The relevance or presence of alternate gene products can vary:
The RNA segments of the viral genome have complementary base sequences at the terminal ends, allowing them to bond to each other with hydrogen bonds. Transcription of the viral sense genome can only proceed after the PB2 protein binds to host capped RNAs, allowing for the PA subunit to cleave several nucleotides after the cap. This host-derived cap and accompanied nucleotides serve as the primer for viral transcription initiation. Transcription proceeds along the vRNA until a stretch of several uracil bases is reached, initiating a 'stuttering' whereby the nascent viral mRNA is poly-adenylated, producing a mature transcript for nuclear export and translation by host machinery.
The RNA synthesis takes place in the cell nucleus, while the synthesis of proteins takes place in the cytoplasm. Once the viral proteins are assembled into virions, the assembled virions leave the nucleus and migrate towards the cell membrane. The host cell membrane has patches of viral transmembrane proteins and an underlying layer of the M1 protein which assist the assembled virions to budding through the membrane, releasing finished enveloped viruses into the extracellular fluid.

Multiplicity reactivation

Influenza virus is able to undergo multiplicity reactivation after inactivation by UV radiation, or by ionizing radiation. If any of the eight RNA strands that make up the genome contains damage that prevents replication or expression of an essential gene, the virus is not viable when it alone infects a cell. However, when two or more damaged viruses infect the same cell, viable progeny viruses can be produced provided each of the eight genomic segments is present in at least one undamaged copy. That is, multiplicity reactivation can occur.
Upon infection, influenza virus induces a host response involving increased production of reactive oxygen species, and this can damage the virus genome. If, under natural conditions, virus survival is ordinarily vulnerable to the challenge of oxidative damage, then multiplicity reactivation is likely selectively advantageous as a kind of genomic repair process. It has been suggested that multiplicity reactivation involving segmented RNA genomes may be similar to the earliest evolved form of sexual interaction in the RNA world that likely preceded the DNA world.

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.
Genetic factors in distinguishing between "human flu viruses" and "avian influenza viruses" include:
Human flu symptoms usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, breathing problems and pneumonia that may be fatal. The severity of the infection will depend in 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. Follow-up studies on the impact of statins on influenza virus replication show that pre-treatment of cells with atorvastatin suppresses virus growth in culture.
Highly pathogenic H5N1 avian influenza in a human is far worse, killing 50% of humans who catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.
The influenza A virus subtypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:
;H1N1
;H1N2
;H2N2
;H3N2
;H5N1
;H5N2
;H5N9
;H7N2
;H7N3
;H7N7
;H7N9
;H9N2
;H10N7

Evolution

According to Jeffery Taubenberger:
Researchers from the National Institutes of Health used data from the Influenza Genome Sequencing Project and concluded that during the ten-year period examined, most of the time the hemagglutinin gene in H3N2 showed no significant excess of mutations in the antigenic regions while an increasing variety of strains accumulated. This resulted in one of the variants eventually achieving higher fitness, becoming dominant, and in a brief interval of rapid evolution, rapidly sweeping through the population and eliminating most other variants.
In the short-term evolution of influenza A virus, a 2006 study found that stochastic, or random, processes are key factors. Influenza A virus HA antigenic evolution appears to be characterized more by punctuated, sporadic jumps as opposed to a constant rate of antigenic change. Using phylogenetic analysis of 413 complete genomes of human influenza A viruses that were collected throughout the state of New York, the authors of Nelson et al. 2006 were able to show that genetic diversity, and not antigenic drift, shaped the short-term evolution of influenza A via random migration and reassortment. The evolution of these viruses is dominated more by the random importation of genetically different viral strains from other geographic locations and less by natural selection. Within a given season, adaptive evolution is infrequent and had an overall weak effect as evidenced from the data gathered from the 413 genomes. Phylogenetic analysis revealed the different strains were derived from newly imported genetic material as opposed to isolates that had been circulating in New York in previous seasons. Therefore, the gene flow in and out of this population, and not natural selection, was more important in the short term.

Other animals

;Avian influenza
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 wildfowl 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.
Wild aquatic birds are the natural hosts for a large variety of influenza A viruses. Occasionally, viruses are transmitted from these birds to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.
H5N1 has been shown to be transmitted to tigers, leopards, and domestic cats that were fed uncooked domestic fowl with the virus. H3N8 viruses from horses have crossed over and caused outbreaks in dogs. Laboratory mice have been infected successfully with a variety of avian flu genotypes.
Influenza A viruses spread in the air and in manure, and survives longer in cold weather. They can also be transmitted by contaminated feed, water, equipment, and clothing; however, there is no evidence the virus can survive in well-cooked meat. Symptoms in animals vary, but virulent strains can cause death within a few days. Avian influenza viruses that the World Organisation for Animal Health and others test for to control poultry disease include H5N1, H7N2, H1N7, H7N3, H13N6, H5N9, H11N6, H3N8, H9N2, H5N2, H4N8, H10N7, H2N2, H8N4, H14N5, H6N5, and H12N5.
;Known outbreaks of highly pathogenic flu in poultry 1959–2003
YearAreaAffectedSubtype
1959ScotlandChickenH5N1
1963EnglandTurkeyH7N3
1966Ontario TurkeyH5N9
1976Victoria ChickenH7N7
1979GermanyChickenH7N7
1979EnglandTurkeyH7N7
1983Pennsylvania *Chicken, turkeyH5N2
1983IrelandTurkeyH5N8
1985Victoria ChickenH7N7
1991EnglandTurkeyH5N1
1992Victoria ChickenH7N3
1994Queensland ChickenH7N3
1994Mexico*ChickenH5N2
1994Pakistan*ChickenH7N3
1997New South Wales ChickenH7N4
1997Hong Kong *ChickenH5N1
1997ItalyChickenH5N2
1999Italy*TurkeyH7N1
2002Hong Kong ChickenH5N1
2002ChileChickenH7N3
2003Netherlands*ChickenH7N7

*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.
More than 400 harbor seal deaths were recorded in New England between December 1979 and October 1980, from acute pneumonia caused by the influenza virus, A/Seal/Mass/1/180.
;Swine flu
;Horse flu
;Dog flu
;Bat flu
;H3N8