Antigenic shift

Antigenic shift is the process by which two or more different strains of a virus, or strain of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains. The term is often applied specifically to influenza, as that is the best-known example, but the process is also known to occur with other viruses, such as visna virus in sheep.[1] Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change.

Antigenic shift is contrasted with antigenic drift, which is the natural mutation over time of known strains of influenza (or other things, in a more general sense) which may lead to a loss of immunity, or in vaccine mismatch. Antigenic drift occurs in all types of influenza including influenzavirus A, influenza B and influenza C. Antigenic shift, however, occurs only in influenzavirus A because it infects more than just humans.[2] Affected species include other mammals and birds, giving influenza A the opportunity for a major reorganization of surface antigens. Influenza B and C principally infect humans, minimizing the chance that a reassortment will change its phenotype drastically.[3]

Antigenic shift is important for the emergence of new viral pathogens as it is a pathway that viruses may follow to enter a new niche. It could occur with primate viruses and may be a factor for the appearance of new viruses in the human species such as HIV. Due to the structure of its genome, HIV does not undergo reassortment, but it does recombine freely and via superinfection HIV can produce recombinant HIV strains that differ significantly from their ancestors.

AntigenicShift HiRes vector
NIAID illustration of potential influenza genetic reassortment

Role in transmission of influenza viruses from non-human animals to people

Influenza A viruses are found in many different animals, including ducks, chickens, pigs, humans, whales, horses, and seals.[3] Influenza B viruses circulate widely principally among humans, though it has recently been found in seals.[4] Flu strains are named after their types of hemagglutinin and neuraminidase surface proteins (of which there are 18 and 9 respectively), so they will be called, for example, H3N2 for type-3 hemagglutinin and type-2 neuraminidase. Some strains of avian influenza (from which all other strains of influenza A are believed to stem[2]) can infect pigs or other mammalian hosts. When two different strains of influenza infect the same cell simultaneously, their protein capsids and lipid envelopes are removed, exposing their RNA, which is then transcribed to mRNA. The host cell then forms new viruses that combine their antigens; for example, H3N2 and H5N1 can form H5N2 this way. Because the human immune system has difficulty recognizing the new influenza strain, it may be highly dangerous, and result in a new pandemic.[3]

Influenza viruses which have undergone antigenic shift have caused the Asian Flu pandemic of 1957, the Hong Kong Flu pandemic of 1968, and the Swine Flu scare of 1976. Until recently, such combinations were believed to have caused the infamous Spanish flu outbreak of 1918 which killed 40~100 million people worldwide; however more recent research suggests the 1918 pandemic was caused by the antigenic drift of a fully avian virus to a form that could infect humans efficiently.[5][6] The most recent 2009 H1N1 outbreak was a result of antigenic shift and reassortment between human, avian, and swine viruses.[7] One increasingly worrying situation is the possible antigenic shift between avian influenza and human influenza. This antigenic shift could cause the formation of a highly virulent virus.

In the marine ecosystem

In terms of virology, the marine ecosystem has been largely unstudied, but due to its extraordinary volume, high viral density (100 million viruses per mL in coastal waters, 3 million per mL in the deep sea)[8] and high cell lysing rate (as high as 20% on average), marine viruses' antigenic shift and genetic recombination rates must be quite high.[9] This is most striking when one considers that the coevolution of prokaryotes and viruses in the aquatic environment has been going on since before eukaryotes appeared on earth.

See also


  1. ^ Narayan, O; Griffin, DE; Chase, J (1977). "Antigenic shift of visna virus in persistently infected sheep". Science. 197 (4301): 376–378. doi:10.1126/science.195339. PMID 195339.)
  2. ^ a b Treanor, John (15 January 2004). "Influenza vaccine--outmaneuvering antigenic shift and drift". New England Journal of Medicine. 350 (3): 218–220. doi:10.1056/NEJMp038238. PMID 14724300.
  3. ^ a b c Zambon, Maria C. (November 1999). "Epidemiology and pathogenesis of influenza" (PDF). Journal of Antimicrobial Chemotherapy. 44 (Supp B): 3–9. doi:10.1093/jac/44.suppl_2.3. PMID 10877456. Retrieved 9 January 2008.
  4. ^ Carrington, Damian (11 May 2000). "Seals pose influenza threat". BBC.
  5. ^ Aoki, FY; Sitar, DS (January 1988). "Clinical pharmacokinetics of amantadine hydrochloride". Clinical Pharmacokinetics. 14 (1): 35–51. doi:10.2165/00003088-198814010-00003. PMID 3280212.
  6. ^ Johnson, NP; Mueller, J (Spring 2002). "Updating the accounts: global mortality of the 1918-1920 "Spanish" influenza pandemic". Bulletin of the History of Medicine. 76 (1): 105–115. doi:10.1353/bhm.2002.0022. PMID 11875246.
  7. ^ Smith, G. J. D.; Vijaykrishna, D.; Bahl, J.; Lycett, S. J.; Worobey, M.; Pybus, O. G.; Ma, S. K.; Cheung, C. L.; Raghwani, J.; Bhatt, S.; Peiris, J. S. M.; Guan, Y.; Rambaut, A. (2009). "Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic". Nature. 459 (7250): 1122–1125. doi:10.1038/nature08182. PMID 19516283.
  8. ^ Denny, How the Ocean Works: An Introduction to Oceanography (2008). How the Ocean Works (illustrated ed.). Princeton University Press. ISBN 9780691126470.)
  9. ^ Suttle, CA (2007). "Marine viruses — major players in the global ecosystem". Nature Reviews Microbiology. 5 (10): 801–812. doi:10.1038/nrmicro1750. PMID 17853907.

Further reading

External links

1968 flu pandemic

The 1968 flu pandemic was a category 2 flu pandemic whose outbreak in 1968 and 1969 killed an estimated one million people worldwide. It was caused by an H3N2 strain of the influenza A virus, descended from H2N2 through antigenic shift, a genetic process in which genes from multiple subtypes reassorted to form a new virus. Because it originated in Hong Kong, the pandemic is also referred to as Hong Kong flu.

Antigenic drift

Antigenic drift is a mechanism for variation in viruses that involves the accumulation of mutations within the genes that code for antibody-binding sites. This results in a new strain of virus particles which cannot be inhibited as effectively by the antibodies that were originally targeted against previous strains, making it easier for the virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.

The immune system recognizes viruses when antigens on the surfaces of virus particles bind to immune receptors that are specific for these antigens. This is similar to a lock recognizing a key. After an infection, the body produces many more of these virus-specific immune receptors, which prevent re-infection by this particular strain of the virus and produce acquired immunity. Similarly, a vaccine against a virus works by teaching the immune system to recognize the antigens exhibited by this virus. However, viral genomes are constantly mutating, producing new forms of these antigens. If one of these new forms of an antigen is sufficiently different from the old antigen, it will no longer bind to the receptors of the body cells, and viruses with these new antigens can infect the body cell as it avoids the immunity to the original strain of the virus. When such a change occurs, people who have had the illness in the past are therefore not immune to the new strain of the virus (as the new strain of the virus has a different antigen which the body cell cannot recognise) and thus the vaccines against the original virus will be less effective against the illness. Two processes drive the antigens to change: antigenic drift and antigenic shift, antigenic drift being the more common. The rate of antigenic drift is dependent on two characteristics: the duration of the epidemic, and the strength of host immunity. A longer epidemic allows for selection pressure to continue over an extended period of time and stronger host immune responses increase selection pressure for development of novel antigens.

Antigenic variation

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

Avian influenza

Avian influenza—known informally as avian flu or bird flu is a variety of influenza caused by viruses adapted to birds. The type with the greatest risk is highly pathogenic avian influenza (HPAI). Bird flu is similar to swine flu, dog flu, horse flu and human flu as an illness caused by strains of influenza viruses that have adapted to a specific host. Out of the three types of influenza viruses (A, B, and C), influenza A virus is a zoonotic infection with a natural reservoir almost entirely in birds. Avian influenza, for most purposes, refers to the influenza A virus.

Though influenza A is adapted to birds, it can also stably adapt and sustain person-to person transmission. Recent influenza research into the genes of the Spanish flu virus shows it to have genes adapted from both human and avian strains. Pigs can also be infected with human, avian, and swine influenza viruses, allowing for mixtures of genes (reassortment) to create a new virus, which can cause an antigenic shift to a new influenza A virus subtype which most people have little to no immune protection against.Avian influenza strains are divided into two types based on their pathogenicity: high pathogenicity (HP) or low pathogenicity (LP). The most well-known HPAI strain, H5N1, appeared in China in 1996, and also has low pathogenic strains found in North America. Companion birds in captivity are unlikely to contract the virus and there has been no report of a companion bird with avian influenza since 2003. Pigeons can contract avian strains, but rarely become ill and are incapable of transmitting the virus efficiently to humans or other animals.Between early 2013 and early 2017, 916 lab-confirmed human cases of H7N9 were reported to the World Health Organization (WHO). On 9 January 2017, the National Health and Family Planning Commission of China reported to WHO 106 cases of H7N9 which occurred from late November through late December, including 35 deaths, 2 potential cases of human-to-human transmission, and 80 of these 106 persons stating that they have visited live poultry markets. The cases are reported from Jiangsu (52), Zhejiang (21), Anhui (14), Guangdong (14), Shanghai (2), Fujian (2) and Hunan (1). Similar sudden increases in the number of human cases of H7N9 have occurred in previous years during December and January.

Evolution of influenza

The virus causing influenza is one of the best known pathogens found in various species. In particular, the virus is found in birds as well as mammals including horses, pigs, and humans. The phylogeny, or the evolutionary history of a particular species, is an important component when analyzing the evolution of influenza. Phylogenetic trees are graphical models of the relationships between various species. They can be used to trace the virus back to particular species and show how organisms that look so different may be so closely related.

Glossary of virology

This glossary of virology is a list of definitions of terms and concepts used in the study of virology, particularly in the description of viruses and their actions.

Hemagglutinin (influenza)

Influenza hemagglutinin (HA) or haemagglutinin[p] (British English) is a homotrimeric glycoprotein found on the surface of influenza viruses and integral to its infectivity.

Hemagglutinin is a Class I Fusion Protein, having multifunctional activity as both an attachment factor and membrane fusion protein. Therefore, HA is responsible for binding Influenza virus to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes, following which event the virus is internalised. Secondarily, HA is responsible for the fusion of the viral envelope with the late endosomal membrane once exposed to low pH (5.0-5.5).The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.


Influenza, commonly known as the flu, is an infectious disease caused by an influenza virus. Symptoms can be mild to severe. The most common symptoms include: high fever, runny nose, sore throat, muscle pains, headache, coughing, sneezing, and feeling tired. These symptoms typically begin two days after exposure to the virus and most last less than a week. The cough, however, may last for more than two weeks. In children, there may be diarrhea and vomiting, but these are not common in adults. Diarrhea and vomiting occur more commonly in gastroenteritis, which is an unrelated disease and sometimes inaccurately referred to as "stomach flu" or the "24-hour flu". Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and worsening of previous health problems such as asthma or heart failure.Three of the four types of influenza viruses affect humans: Type A, Type B, and Type C. Type D has not been known to infect humans, but is believed to have the potential to do so. Usually, the virus is spread through the air from coughs or sneezes. This is believed to occur mostly over relatively short distances. It can also be spread by touching surfaces contaminated by the virus and then touching the mouth or eyes. A person may be infectious to others both before and during the time they are showing symptoms. The infection may be confirmed by testing the throat, sputum, or nose for the virus. A number of rapid tests are available; however, people may still have the infection even if the results are negative. A type of polymerase chain reaction that detects the virus's RNA is more accurate.Frequent hand washing reduces the risk of viral spread. Wearing a surgical mask is also useful. Yearly vaccinations against influenza are recommended by the World Health Organization for those at high risk. The vaccine is usually effective against three or four types of influenza. It is usually well-tolerated. A vaccine made for one year may not be useful in the following year, since the virus evolves rapidly. Antiviral drugs such as the neuraminidase inhibitor oseltamivir, among others, have been used to treat influenza. The benefit of antiviral drugs in those who are otherwise healthy do not appear to be greater than their risks. No benefit has been found in those with other health problems.Influenza spreads around the world in yearly outbreaks, resulting in about three to five million cases of severe illness and about 250,000 to 500,000 deaths. About 20% of unvaccinated children and 10% of unvaccinated adults are infected each year. In the northern and southern parts of the world, outbreaks occur mainly in the winter, while around the equator, outbreaks may occur at any time of the year. Death occurs mostly in the young, the old, and those with other health problems. Larger outbreaks known as pandemics are less frequent. In the 20th century, three influenza pandemics occurred: Spanish influenza in 1918 (~50 million deaths), Asian influenza in 1957 (two million deaths), and Hong Kong influenza in 1968 (one million deaths). The World Health Organization declared an outbreak of a new type of influenza A/H1N1 to be a pandemic in June 2009. Influenza may also affect other animals, including pigs, horses, and birds.

Influenza A virus subtype H2N2

H2N2 is a subtype of the influenza A virus. H2N2 has mutated into various strains including the Asian flu strain (now extinct in the wild), H3N2, and various strains found in birds. It is also suspected of causing a human pandemic in 1889.

The geographic spreading of the 1889 Russian flu have been studied and published.

Influenza A virus subtype H3N2

Influenza A virus subtype H3N2 (A/H3N2) is a subtype of viruses that causes influenza (flu). H3N2 viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. In years in which H3N2 is the predominate strain, there are more hospitalizations.

Influenza C virus

Influenza C virus is the species in the genus Influenzavirus C, in the virus family Orthomyxoviridae, which like other influenza viruses, causes influenza.

Influenza C viruses are known to infect humans and pigs.Flu due to the Type C species is rare compared to Types A or B, but can be severe and can cause local epidemics. Type C has 7 RNA segments and encodes 9 proteins, while Types A and B have 8 RNA segments and encode at least 10 proteins.

Influenza D virus

Influenza D virus is a species in the virus genus Influenzavirus D, in the family Orthomyxoviridae, that causes influenza.

Influenza D viruses are known to infect pigs and cattle; no human infections from this virus have been observed. First isolated from pigs in 2011, the virus was categorized as a new genus of Orthomyxoviridae in 2016, distinct from the previously-known Influenzavirus C genus; before then, Influenza D virus was thought to be a subtype of Influenzavirus C.Cases of infections from the Type D virus are rare compared to Types A, B, and C. Similar to Type C, Type D has 7 RNA segments and encodes 9 proteins, while Types A and B have 8 RNA segments and encode at least 10 proteins.


Orthomyxoviridae (ὀρθός, orthós, Greek for "straight"; μύξα, mýxa, Greek for "mucus") is a family of RNA viruses. It includes seven genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Influenzavirus D, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in vertebrates, including birds (see also avian influenza), humans, and other mammals. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates, such as ticks and mosquitoes.The four genera of Influenza virus, which are identified by antigenic differences in their nucleoprotein and matrix protein, infect vertebrates as follows:

Influenzavirus A infects humans, other mammals, and birds, and causes all flu pandemics

Influenzavirus B infects humans and seals

Influenzavirus C infects humans, pigs, and dogs.

Influenzavirus D infects pigs and cattle


Paramyxoviridae is a family of viruses in the order Mononegavirales. Vertebrates serve as natural hosts; no known plants serve as vectors. Currently, 49 species are placed in this family, divided among seven genera. Diseases associated with this negative-sense, single-stranded RNA virus family include measles, mumps, and respiratory tract infections.


Reassortment is the mixing of the genetic material of a species into new combinations in different individuals. Several different processes contribute to reassortment, including assortment of chromosomes, and chromosomal crossover. It is particularly used when two similar viruses that are infecting the same cell exchange genetic material. In particular, reassortment occurs among influenza viruses, whose genomes consist of eight distinct segments of RNA. These segments act like mini-chromosomes, and each time a flu virus is assembled, it requires one copy of each segment.

If a single host (a human, a chicken, or other animal) is infected by two different strains of the influenza virus, then it is possible that new assembled viral particles will be created from segments whose origin is mixed, some coming from one strain and some coming from another. The new reassortant strain will share properties of both of its parental lineages.

Reassortment is responsible for some of the major genetic shifts in the history of the influenza virus. The 1957 and 1968 pandemic flu strains were caused by reassortment between an avian virus and a human virus, whereas the H1N1 virus responsible for the 2009 swine flu outbreak has an unusual mix of swine, avian and human influenza genetic sequences.

Robert Webster (virologist)

Robert Gordon Webster (born 5 July 1932 in Balclutha, New Zealand) is an avian influenza authority who correctly posited that pandemic strains of flu arise from genes in flu virus strains in nonhumans; for example, via a reassortment of genetic segments (antigenic shift) between viruses in humans and nonhumans (especially birds) rather than by mutations (antigenic drift) in annual human flu strains.

Strain (biology)

In biology, a strain is a low-level taxonomic rank used at the intraspecific level (within a species). Strains are often seen as inherently artificial concepts, characterized by a specific intent for genetic isolation. This is most easily observed in microbiology where strains are derived from a single cell colony and are typically quarantined by the physical constraints of a Petri dish. Strains are also commonly referred to within virology, botany, and with rodents used in experimental studies.

Viral neuraminidase

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins and are required for influenza virus replication.

When influenza virus replicates, it attaches to the interior cell surface using hemagglutinin, a molecule found on the surface of the virus that binds to sialic acid groups. Sialic acids are found on various glycoproteins at the host cell surface, and the virus exploits these groups to bind the host cell. In order for the virus to be released from the cell, neuraminidase must enzymatically cleave the sialic acid groups from host glycoproteins.

Since the cleavage of the sialic groups is an integral part of influenza replication, blocking the function of neuraminidase with neuraminidase inhibitors is an effective way to treat influenza.

A single hemagglutinin-neuraminidase protein can combine neuraminidase and hemagglutinin functions, such as in mumps virus and human parainfluenza virus.


A virus is a small infectious agent that replicates only inside the living cells of an organism. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea.Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants, and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898, about 5,000 virus species have been described in detail, although there are millions of types. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity. The study of viruses is known as virology, a sub-speciality of microbiology.

While not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles. These viral particles, also known as virions, consist of: (i) the genetic material made from either DNA or RNA, long molecules that carry genetic information; (ii) a protein coat, called the capsid, which surrounds and protects the genetic material; and in some cases (iii) an envelope of lipids that surrounds the protein coat. The shapes of these virus particles range from simple helical and icosahedral forms for some virus species to more complex structures for others. Most virus species have virions that are too small to be seen with an optical microscope. The average virion is about one one-hundredth the size of the average bacterium.

The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids—pieces of DNA that can move between cells—while others may have evolved from bacteria. In evolution, viruses are an important means of horizontal gene transfer, which increases genetic diversity. Viruses are considered by some to be a life form, because they carry genetic material, reproduce, and evolve through natural selection, but lack key characteristics (such as cell structure) that are generally considered necessary to count as life. Because they possess some but not all such qualities, viruses have been described as "organisms at the edge of life", and as replicators.Viruses spread in many ways; viruses in plants are often transmitted from plant to plant by insects that feed on plant sap, such as aphids; viruses in animals can be carried by blood-sucking insects. These disease-bearing organisms are known as vectors. Influenza viruses are spread by coughing and sneezing. Norovirus and rotavirus, common causes of viral gastroenteritis, are transmitted by the faecal–oral route and are passed from person to person by contact, entering the body in food or water. HIV is one of several viruses transmitted through sexual contact and by exposure to infected blood. The variety of host cells that a virus can infect is called its "host range". This can be narrow, meaning a virus is capable of infecting few species, or broad, meaning it is capable of infecting many.Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral infection. Some viruses, including those that cause AIDS and viral hepatitis, evade these immune responses and result in chronic infections. Several antiviral drugs have been developed.

Viral life cycle
By host


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