influenza a virus influenza a virus influenza a virus (iav) is a pathogen that causes the flu in birds and some mammals, including humans. it is an rna virus whose subtypes have been isolated from wild birds. occasionally, it is transmitted from wild to domestic birds, and this may cause severe disease, outbreaks, or human influenza pandemics. influenza a virus structure of influenza a virus tem micrograph of influenza a viruses virus classification (unranked): virus realm: riboviria kingdom: orthornavirae phylum: negarnaviricota class: insthoviricetes order: articulavirales family: orthomyxoviridae genus: alphainfluenzavirus species: influenza a virus subtypes see text each virus subtype has mutated into a variety of strains with differing pathogenic profiles; some may cause disease only in one species but others to multiple ones. 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. in 2011, researchers reported the discovery of an antibody effective against all types of the influenza a virus. variants and subtypes diagram of influenza nomenclature influenza a virus is the only species of the genus alphainfluenzavirus of the virus family orthomyxoviridae. it is an rna virus categorized into subtypes based on the type of two proteins on the surface of the viral envelope: h = hemagglutinin, a protein that causes red blood cells to agglutinate. n = neuraminidase, an enzyme that cleaves the glycosidic bonds of the monosaccharide sialic acid (previously called neuraminic acid). 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 (h) protein and a type 1 neuraminidase (n) 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 (example fujian flu virus-like); according to their typical host (example human flu virus); according to their subtype (example h3n2); and according to their deadliness (example lp, low pathogenic). so a flu from a virus similar to the isolate a/fujian/411/2002(h3n2) is called fujian flu, human flu, and h3n2 flu. variants are sometimes named according to the species (host) in which the strain is endemic or to which it is adapted. the main variants named using this convention are: bird flu human flu swine influenza equine influenza canine influenza bat influenza 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 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 main article: flu season the annual flu (also called "seasonal flu" or "human 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 (ha) 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 fi6, 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 a viruses are negative-sense, single-stranded, segmented rna virus. the several subtypes are labeled according to an h number (for the type of hemagglutinin) and an n number (for the type of neuraminidase). there are 18 different known h antigens (h1 to h18) and 11 different known n antigens (n1 to n11). h17n10 was isolated from fruit bats in 2012. h18n11 was discovered in a peruvian bat in 2013.a transmission electron micrograph (tem) of the reconstructed 1918 pandemic influenza virus. the bottom structure represents membrane debris from the cells used to amplify the virus. pictured are the 'elliptical' particles representing the smallest particles produced by influenza virus. purification techniques often deform the particles without proper fixation protocols, leading to 'spherical' appearance. filamentous or intermediate sized particles simply extend along the long axis on the opposite side of the genome segments.influenza type a viruses are very similar in structure to influenza viruses types b, c, and d. the virus particle (also called the virion) 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 (ha) and neuraminidase (na). 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 (including humans, animals, plants, and bacteria) 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 (protein). 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. influenza a virus structure 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: segment 1 encodes rna polymerase subunit (pb2). segment 2 encodes rna polymerase subunit (pb1) and the pb1-f2 protein, which induces cell death, by using different reading frames from the same rna segment. segment 3 encodes rna polymerase subunit (pa) and the pa-x protein, which has a role in host transcription shutoff. segment 4 encodes for ha (hemagglutinin). about 500 molecules of hemagglutinin are needed to make one virion. ha determines the extent and severity of a viral infection in a host organism. segment 5 encodes np, which is a nucleoprotein. segment 6 encodes na (neuraminidase). about 100 molecules of neuraminidase are needed to make one virion. segment 7 encodes two matrix proteins (m1 and m2) by using different reading frames from the same rna segment. about 3,000 matrix protein molecules are needed to make one virion. segment 8 encodes two distinct non-structural proteins (ns1 and nep) by using different reading frames from the same rna segment. influenza a virus replication cycle 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 (vrna) 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 (ha, na, and m2) 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. the subtypes of influenza a virus are estimated to have diverged 2,000 years ago. influenza viruses a and b are estimated to have diverged from a single ancestor around 4,000 years ago, while the ancestor of influenza viruses a and b and the ancestor of influenza virus c are estimated to have diverged from a common ancestor around 8,000 years ago. 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 (a single infection). however, when two or more damaged viruses infect the same cell (multiple infection), 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 timeline of flu pandemics and epidemics caused by influenza a 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: 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 binds alpha 2–3 sialic acid receptors, while human influenza ha binds 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, breathing problems and