Influenza A and influenza B viruses genome, mRNA, and virion diagram
Virus classification e
  • Alphainfluenzavirus
  • Betainfluenzavirus
  • Deltainfluenzavirus
  • Gammainfluenzavirus
  • Isavirus
  • Quaranjavirus
  • Thogotovirus

Orthomyxoviridae (from Greek ὀρθός, orthós 'straight' + μύξα, mýxa 'mucus')[1] is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Deltainfluenzavirus, Gammainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds (see also avian influenza) and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates (such as ticks and mosquitoes).[2][3][4] The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).

The four genera of Influenza virus that infect vertebrates, which are identified by antigenic differences in their nucleoprotein and matrix protein, are as follows:


Influenza A virus structure

The influenzavirus virion is pleomorphic; the viral envelope can occur in spherical and filamentous forms. In general, the virus's morphology is ellipsoidal with particles 100–120 nm in diameter, or filamentous with particles 80–100 nm in diameter and up to 20 µm long.[5] There are approximately 500 distinct spike-like surface projections in the envelope each projecting 10–14 nm from the surface with varying surface densities. The major glycoprotein (HA) spike is interposed irregularly by clusters of neuraminidase (NA) spikes, with a ratio of HA to NA of about 10 to 1.[6]

The viral envelope composed of a lipid bilayer membrane in which the glycoprotein spikes are anchored encloses the nucleocapsids; nucleoproteins of different size classes with a loop at each end; the arrangement within the virion is uncertain. The ribonuclear proteins are filamentous and fall in the range of 50–130 nm long and 9–15 nm in diameter with helical symmetry.


Influenzavirus genomes. Segments translate to polymerase (PB1, PB2, and PA), hemagglutinin (HA), neuramindase (NA), nucleoprotein (NP), membrane protein (M), and non-structural protein (NS).

Viruses of the family Orthomyxoviridae contain six to eight segments of linear negative-sense single stranded RNA. They have a total genome length that is 10,000–14,600 nucleotides (nt).[7] The influenza A genome, for instance, has eight pieces of segmented negative-sense RNA (13.5 kilobases total).[8]

The best-characterised of the influenzavirus proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.[9] In contrast, neuraminidase is an enzyme involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. The hemagglutinin (H) and neuraminidase (N) proteins are key targets for antibodies and antiviral drugs,[10][11] and they are used to classify the different serotypes of influenza A viruses, hence the H and N in H5N1.

The genome sequence has terminal repeated sequences; repeated at both ends. Terminal repeats at the 5′-end 12–13 nucleotides long. Nucleotide sequences of 3′-terminus identical; the same in genera of same family; most on RNA (segments), or on all RNA species. Terminal repeats at the 3′-end 9–11 nucleotides long. Encapsidated nucleic acid is solely genomic. Each virion may contain defective interfering copies. In Influenza A (H1N1) PB1-F2 is produced from an alternative reading frame in PB1. The M and NS genes produce two different genes via alternative splicing.[12]

Replication cycle

Infection and replication of the influenza virus. The steps in this process are discussed in the text.

Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Influenza can also be transmitted by saliva, nasal secretions, feces and blood. Infections occur through contact with these bodily fluids or with contaminated surfaces. Out of a host, flu viruses can remain infectious for about one week at human body temperature, over 30 days at 0 °C (32 °F), and indefinitely at very low temperatures (such as lakes in northeast Siberia). They can be inactivated easily by disinfectants and detergents.[13][14][15]

The viruses bind to a cell through interactions between its hemagglutinin glycoprotein and sialic acid sugars on the surfaces of epithelial cells in the lung and throat (Stage 1 in infection figure).[16] The cell imports the virus by endocytosis. In the acidic endosome, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, releasing the viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA polymerase into the cytoplasm (Stage 2).[17] These proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA polymerase begins transcribing complementary positive-sense cRNA (Steps 3a and b).[18] The cRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly synthesised viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.[19]

Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA transcriptase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).[20] As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell.[16] After the release of new influenza virus, the host cell dies.

Transcription of mRNAs initiated by viral polymerase using cap snatching

Orthomyxoviridae viruses are one of two RNA viruses that replicate in the nucleus (the other being retroviridae). This is because the machinery of orthomyxo viruses cannot make their own mRNAs. They use cellular RNAs as primers for initiating the viral mRNA synthesis in a process known as cap snatching.[21] Once in the nucleus, the RNA Polymerase Protein PB2 finds a cellular pre-mRNA and binds to its 5′ capped end. Then RNA Polymerase PA cleaves off the cellular mRNA near the 5′ end and uses this capped fragment as a primer for transcribing the rest of the viral RNA genome in viral mRNA.[22] This is due to the need of mRNA to have a 5′ cap in order to be recognized by the cell's ribosome for translation.

Since RNA proofreading enzymes are absent, the RNA-dependent RNA transcriptase makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly manufactured influenza virus will contain a mutation in its genome.[23] The separation of the genome into eight separate segments of vRNA allows mixing (reassortment) of the genes if more than one variety of influenza virus has infected the same cell (superinfection). The resulting alteration in the genome segments packaged into viral progeny confers new behavior, sometimes the ability to infect new host species or to overcome protective immunity of host populations to its old genome (in which case it is called an antigenic shift).[10]


In a phylogenetic-based taxonomy, the category RNA virus includes the subcategory negative-sense ssRNA virus, which includes the order Articulavirales, and the family Orthomyxoviridae. The genera-associated species and serotypes of Orthomyxoviridae are shown in the following table.

Orthomyxovirus Genera, Species, and Serotypes
GenusSpecies (* indicates type species)Serotypes or SubtypesHosts
AlphainfluenzavirusInfluenza A virus*H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7Human, pig, bird, horse, bat
BetainfluenzavirusInfluenza B virus*Victoria, Yamagata[24]Human, seal
GammainfluenzavirusInfluenza C virus*Human, pig, dog
DeltainfluenzavirusInfluenza D virus*Pig, cattle
IsavirusInfectious salmon anemia virus*Atlantic salmon
ThogotovirusThogotovirus*Tick, mosquito, mammal (including human)
Dhori virusBatken virus, Bourbon virus, Jos virus
Quaranfil virus,* Johnston Atoll virus


There are four genera of influenza virus, each containing only a single species, or type. Influenza A and C infect a variety of species (including humans), while influenza B almost exclusively infects humans, and influenza D infects cattle and pigs.[26][27][28]

Influenza A

Diagram of influenza nomenclature

Influenza A viruses are further classified, based on the viral surface proteins hemagglutinin (HA or H) and neuraminidase (NA or N). Sixteen H subtypes (or serotypes) and nine N subtypes of influenza A virus have been identified.

Further variation exists; thus, specific influenza strain isolates are identified by a standard nomenclature specifying virus type, geographical location where first isolated, sequential number of isolation, year of isolation, and HA and NA subtype.[29][30]

Examples of the nomenclature are:

  1. A/Brisbane/59/2007 (H1N1)
  2. A/Moscow/10/99 (H3N2).

The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

  • H1N1 caused "Spanish flu" in 1918 and "Swine flu" in 2009.[31]
  • H2N2 caused "Asian Flu".
  • H3N2 caused "Hong Kong Flu".
  • H5N1, "avian" or "bird flu".[32]
  • H7N7 has unusual zoonotic potential.[33]
  • H1N2 infects pigs and humans.[34]
  • H9N2, H7N2, H7N3, H10N7.
Known flu pandemics[10][35][36]
Name of pandemicDateDeathsCase fatality rateSubtype involvedPandemic Severity Index
1889–1890 flu pandemic
(Asiatic or Russian Flu)[37]
1889–18901 million0.15%Possibly H3N8
or H2N2
1918 flu pandemic
(Spanish flu)[38]
1918–192020 to 100 million2%H1N15
Asian Flu1957–19581 to 1.5 million0.13%H2N22
Hong Kong Flu1968–19690.75 to 1 million<0.1%H3N22
Russian flu1977–1978No accurate countN/AH1N1N/A
2009 flu pandemic[39][40]2009–2010105,700–395,600[41]0.03%H1N1N/A

Influenza B

Host range of influenza viruses

Influenza B virus is almost exclusively a human pathogen, and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal.[42] This type of influenza mutates at a rate 2–3 times lower than type A[43] and consequently is less genetically diverse, with only one influenza B serotype.[26] As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.[44] This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.[45]

Influenza C

The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.[46] However, influenza C is less common than the other types and usually causes mild disease in children.[47][48]

Influenza D

This is a genus that was classified in 2016, the members of which were first isolated in 2011.[49] This genus appears to be most closely related to Influenza C, from which it diverged several hundred years ago.[50] There are at least two extant strains of this genus.[51] The main hosts appear to be cattle, but the virus has been known to infect pigs as well.

Viability and disinfection

Mammalian influenza viruses tend to be labile, but can survive several hours in mucus.[52] Avian influenza virus can survive for 100 days in distilled water at room temperature, and 200 days at 17 °C (63 °F). The avian virus is inactivated more quickly in manure, but can survive for up to 2 weeks in feces on cages. Avian influenza viruses can survive indefinitely when frozen.[52] Influenza viruses are susceptible to bleach, 70% ethanol, aldehydes, oxidizing agents, and quaternary ammonium compounds. They are inactivated by heat of 133 °F (56 °C) for minimum of 60 minutes, as well as by low pH <2.[52]

Vaccination and prophylaxis

Targets of anti-influenza agents that are licensed or under investigation

Vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections. Vaccines are composed of either inactivated or live attenuated virions of the H1N1 and H3N2 human influenza A viruses, as well as those of influenza B viruses. Because the antigenicities of the wild viruses evolve, vaccines are reformulated annually by updating the seed strains.

When the antigenicities of the seed strains and wild viruses do not match, vaccines fail to protect the vaccinees. In addition, even when they do match, escape mutants are often generated.

Drugs available for the treatment of influenza include Amantadine and Rimantadine, which inhibit the uncoating of virions by interfering with M2, and Oseltamivir (marketed under the brand name Tamiflu), Zanamivir, and Peramivir, which inhibit the release of virions from infected cells by interfering with NA. However, escape mutants are often generated for the former drug and less frequently for the latter drug.[53]

See also


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VIH - HIV / SIDA - AIDS viruses.
Rotavirus Reconstruction.jpg
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Computer assisted reconstruction of a rotavirus
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A diagram of influenza viral cell invasion and replication.
Author/Creator: Ahmed Mostafa, Elsayed M. Abdelwhab, Thomas C. Mettenleiter, and Stephan Pleschka, Licence: CC BY 4.0
Schematic structure of influenza A virus (IAV). The envelope of the IAV particle, which is derived from the host cell plasma membrane, contains three trans-membrane proteins; two surface glycoproteins designated as hemagglutinin (HA) and neuraminidase (NA) and the proton channel matrix protein 2 (M2). The matrix protein 1 (M1) underlies the inner surface of the viral envelope and associates with NEP and viral ribonucleoprotein complexes (vRNPs). The eight vRNPs comprise eight negative-strand RNA segments associated with the nucleoprotein (NP) and three RdRp polymerase subunits (PA, PB1, PB2).
Author/Creator: Dan Dou, Rebecca Revol, Henrik Östbye, Hao Wang, and Robert Daniels, Licence: CC BY 4.0
Influenza A and B viruses. (A) Schematic of the eight viral RNA (vRNA) gene segments that comprise the influenza A and B genomes. The 5′ and 3′ untranslated regions (UTRs), which contain the viral promoters, are represented with a line, and the box corresponds to the coding region within each vRNA. (B) Diagram of the viral mRNAs that are transcribed from the IAV (left) and IBV (right) vRNA templates. Boxes indicate the viral gene product encoded by each mRNA and the dashed lines show the alternative splicing of the IAV M and NS transcripts, as well as the IBV NS transcript. Red circles represent the 5′ M7pppG cap, black lines denote the 10–13 nucleotide, host-derived primers that are obtained by the cap-snatching mechanism of the viral polymerase. A(n) corresponds to the 3′ poly-A tail produced by reiterative stuttering of the viral polymerase. The smaller mRNAs (empty boxes) represent transcripts that encode nonessential accessory proteins found in many strains, whereas those that are less prevalent (PB2-S1, M42, and NS3) are not illustrated (6–11). (C) Diagram of an influenza A or B virus. The viral membrane proteins HA, NA, and M2 are shown, along with the eight viral ribonucleoproteins (vRNPs), and the matrix protein M1 that supports the viral envelope. To highlight the vRNP components, the illustration beneath the virus is not to scale. A single vRNA gene segment is shown wrapped around multiple nucleoprotein (NP) copies with the conserved promoter regions in the 5′ and 3′ UTRs forming a helical hairpin, which is bound by a single heterotrimeric viral RNA-dependent RNA polymerase (PB1, PB2, and PA). (D) Top view of an influenza virus cross-section showing the vRNP “1 + 7” configuration. vRNPs are depicted with black circles as it is not known if the positioning of a particular vRNP is conserved or interchangeable.
Author/Creator: Dan Dou, Rebecca Revol, Henrik Östbye, Hao Wang, and Robert Daniels, Licence: CC BY 4.0
Transcription of IAV mRNAs by the viral polymerase. Viral mRNA transcription occurs when the viral ribonucleoproteins reach the host cell nucleus and is assisted by the association of the viral polymerase (PA subunit) with the cellular RNA polymerase II C-terminal domain (RNA pol II CTD). Transcription initiates by a “cap-snatching” mechanism where the PB2 subunit binds to the 5′ cap of a host mRNA (red). Cap binding positions the region of the mRNA 10–13 nucleotides downstream for cleavage by the endonuclease domain in the PA subunit. Following cleavage, a conformational shift repositions the acquired mRNA capped primer to the PB1 subunit where the 3′ end base-pairs with a complimentary sequence at the vRNA 3′ end. Following the priming event, the viral polymerase extends the mRNA transcript. The transcription is terminated by a “reiterative stuttering” process (depicted in the box), which occurs when the polymerase encounters the 5–7 consecutive uracil bases at the vRNA 5′ end. The “reiterative stuttering” function likely involves multiple cycles of dissociation and reannealing, and effectively polyadenylates [A(n)] the viral mRNA by continuously repositioning the elongating 3′ end on the uracil-rich region of the vRNA template.
Author/Creator: Suresh V. Kuchipudi and Ruth H. Nissly, Licence: CC BY 4.0
Host range of influenza viruses by species. Common hosts of more than one species are encompassed in overlapping ovals. Of the numerous hosts which support influenza virus infection, only four (horse, seal, man and pig) are known to be susceptible to more than one species.
Illustration of influenza virus nomenclature system.
DOI 10.5772 55289 image1 w.jpg
Author/Creator: Ewan P. Plant and Zhiping Ye, Licence: CC BY 3.0
Genomes of influenza viruses. A) The ends of the negative strand influenza genomic RNA are complexed with the three polymerase proteins and the remaining sequence is encapsidated with nucleoprotein (vRNP (-)). The positive strand cRNP is similarly complexed. The mRNA is transcribed with a 5’ cap structure and poly-A tail (see main text for details). Figure used with permission from Resa-Infante et al., 2011. B) Schematic of the influenza A virus genome. The bold black lines represent the 3’ and 5’ untranslated regions. The blue and pink boxes represent the major protein coding regions. C) Schematic of the influenza B virus genome. The green and brown boxes represent the major protein coding regions. D) Schematic of the influenza C virus genome. The red and purple boxes represent the major protein coding regions. The protein coding regions are not to scale. Coding regions in a different reading frame are shown above or below each other, coding regions in the same frame are show as contiguous blocks.
Author/Creator: Ahmed Mostafa, Elsayed M. Abdelwhab, Thomas C. Mettenleiter, and Stephan Pleschka, Licence: CC BY 4.0
The targets of anti-influenza agents that are currently licensed or under clinically investigation. Before attachment of the influenza virus particle (IVP) to the host cell, specific neutralizing monoclonal antibodies (mAbs) against conserved domains in HA can prevent viral infection. Enzymatic destruction of the receptor determinant can further prevent IVP-binding to the target cells. After binding of the IVP to host cell sialic-acid receptors the viral life-cycle is continued by receptor-mediated endocytosis, HA-mediated fusion of the viral membrane with vesicular membrane, vRNP uncoating and release into the cytosol. The viral genome is then replicated/transcribed in the nucleus. After the viral mRNA has been translated into proteins some undergo post-translational processing in the cytosol or support genome replication in the nucleus. Newly formed vRNPs are exported from the nucleus and finally progeny virions are assembled and released by budding from the infected cell to infect new cells. These different processes are potential targets for the currently licensed antiviral drugs and others, which are in clinical trials including CR6261, CR8020, MEDI8852, MHAA4549A, VIS-410 (neutralizing Abs); DAS181 (sialidase); Umifenovir (fusion inhibitor); adamantanes (M2 channel blockers); Favipiravir and Ribavirin (RdRp inhibitors); VX-787 (PB2 cap-binding inhibitor); S-033188 (PA endonuclease inhibitor); AVI-7100 (inhibits M1/M2 mRNA-splicing); Nitazoxanide (HA maturation inhibitor); and Oseltamivir, Peramivir, Zanamivir, and Laninamivir (Neuraminidase inhibitors). In addition to its NF-κB inhibition effect, LASAG antagonizes the nuclear export of viral genomes and thereby blocks the assembly and release of mature influenza virus.