This article's lead section may be too long.(May 2012) |
H5N1 genetic structure is the molecular structure of the H5N1 virus's RNA.
H5N1 is an Influenza A virus subtype. Experts believe it might mutate into a form that transmits easily from person to person. If such a mutation occurs, it might remain an H5N1 subtype or could shift subtypes as did H2N2 when it evolved into the Hong Kong Flu strain of H3N2.
H5N1 has mutated [1] through antigenic drift into dozens of highly pathogenic varieties, but all currently belonging to genotype Z of avian influenza virus H5N1. Genotype Z emerged through reassortment in 2002 from earlier highly pathogenic genotypes of H5N1 that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans. [2] The "H5N1 viruses from human infections and the closely related avian viruses isolated in 2004 and 2005 belong to a single genotype, often referred to as genotype Z." [1]
This infection of humans coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population. This panzootic (a disease affecting animals of many species especially over a wide area) outbreak was stopped by the killing of the entire domestic poultry population within the territory. The name H5N1 refers to the subtypes of surface antigens present on the virus: hemagglutinin type 5 and neuraminidase type 1.
Genotype Z of H5N1 is now the dominant genotype of H5N1. Genotype Z is endemic in birds in southeast Asia and represents a long term pandemic threat.
Influenza A viruses have 11 genes on eight separate RNA molecules Orthomyxoviruses:
Two of the most important RNA molecules are HA and PB1. HA creates a surface antigen that is especially important in transmissibility. PB1 creates a viral polymerase molecule that is especially important in virulence.
The HA RNA molecule contains the HA gene, which codes for hemagglutinin, which is an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. Hemagglutinin forms spikes at the surface of flu viruses that function to attach viruses to cells. This attachment is required for efficient transfer of flu virus genes into cells, a process that can be blocked by antibodies that bind to the hemagglutinin proteins.
One genetic factor in distinguishing between human flu viruses and avian flu viruses is that 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. Humans have avian-type receptors at very low densities and chickens have human-type receptors at very low densities. Some isolates taken from H5N1-infected human have been observed to have HA mutations at positions 182, 192, 223, 226, or 228 and these mutations have been shown to influence the selective binding of the virus to those previously mentioned sialic acid avian and/or human cell surface receptors. These are the types of mutations that can change a bird flu virus into a flu pandemic virus.
A 2008 virulence study that mated in a laboratory an avian flu H5N1 virus that circulated in Thailand in 2004 and a human flu H3N2 virus recovered in Wyoming in 2003 produced 63 viruses representing various potential combinations of human and avian influenza A virus genes. One in five were lethal to mice at low doses. The virus that most closely matched H5N1 for virulence was one with the hemagglutinin (HA), the neuraminidase (NA) and the PB1 avian flu virus RNA molecules with their genes combined with the remaining five RNA molecules (PB2, PA, NP, M, and NS) with their genes from the human flu virus. Both the viruses from the 1957 pandemic and 1968 pandemic carried an avian flu virus PB1 gene. The authors suggest that picking up an avian flu virus PB1 gene may be a critical step in a potential flu pandemic virus arising through reassortment." [3]
PB1 codes for the PB1 protein and the PB1-F2 protein. The PB1 protein is a critical component of the viral polymerase. The PB1-F2 protein is encoded by an alternative open reading frame of the PB1 RNA segment and "interacts with 2 components of the mitochondrial permeability transition pore complex, ANT3 and VDCA1, [sensitizing] cells to apoptosis. [...] PB1-F2 likely contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza." [4] This was discovered by Chen et al. and reported in Nature. [5] "After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus." [6]
The Orthomyxovirus family consists of 7 genera:
The "RNA viruses" include the "negative-sense ssRNA viruses" which include the Family "Orthomyxoviridae" which contains five genera, classified by variations in nucleoprotein (NP and M) antigens. One of these is the Genus "Influenzavirus A" which consists of a single species called "Influenza A virus"; one of its subtypes is H5N1.
H5N1 (like the other avian flu viruses) has strains called "highly pathogenic" (HP) and "low-pathogenic" (LP). Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses are generally of lower virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for die-offs of domestic birds in Asia is an HPAI strain; other strains of H5N1 occurring elsewhere in the world are less virulent and, therefore, are classified as LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes. The distinction concerns pathogenicity in poultry, not humans. Normally a highly pathogenic avian virus is not highly pathogenic to either humans or non-poultry birds. This current strain of H5N1 is unusual in being deadly to so many species.
Both "influenza" (meaning flu) and "A" (meaning species type A) can be used as adjectives of the noun "virus" resulting in the noun phrase "influenza A virus"; which when capitalized is the proper noun Influenza A virus which is the name of the species the noun phrase also refers to.
A virus is one type of microscopic parasite that infects cells in biological organisms.
The Orthomyxoviridae are a family of RNA viruses which infect vertebrates. It includes those viruses which cause influenza. Viruses of this family contain 7 to 8 segments of linear negative-sense single-stranded RNA.
"Influenza virus" refers to a subset of Orthomyxoviridae that create influenza. This taxonomic category is not based on phylogenetics.
Influenza A viruses have 10 genes on eight separate RNA molecules, which, for the reasons mentioned above, are named PB2, PB1, PA, HA, NP, NA, M, and NS. HA, NA, and M specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies. (An eleventh recently discovered gene called PB1-F2 sometimes creates a protein but is absent from some influenza virus isolates. [5] ) This segmentation of the influenza genome facilitates genetic recombination by segment reassortment in hosts who are infected with two different influenza viruses at the same time. [1] Influenza A virus is the only species in the Influenzavirus A genus of the family Orthomyxoviridae and are negative sense, single-stranded, segmented RNA viruses.
"The influenza virus RNA polymerase is a multifunctional complex composed of the three viral proteins PB1, PB2 and PA, which, together with the viral nucleoprotein NP, form the minimum complement required for viral mRNA synthesis and replication." [7]
Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The segmentation of the influenza genome facilitates genetic recombination by segment reassortment in hosts who are infected with two different influenza viruses at the same time. H5N1 viruses can reassort genes with other strains that co-infect a host organism, such as a pig, bird, or human, and mutate into a form that can pass easily among humans. This is one of many possible paths to a pandemic.
The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. [25] This doesn't mean that one amino acid substitution can cause a pandemic, but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.
H3N2 ("swine flu") is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. The dominant strain of annual flu virus in January 2006 was H3N2, which is now resistant to the standard antiviral drugs amantadine and rimantadine. The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2.
Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source". [26]
In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert G. Webster of the St. Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". [27] Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.
Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Map
A 2007 study focused on the EMA subclade has shed further light on the EMA mutations. "The 36 new isolates reported here greatly expand the amount of whole-genome sequence data available from recent avian influenza (H5N1) isolates. Before our project, GenBank contained only 5 other complete genomes from Europe for the 2004–2006 period, and it contained no whole genomes from the Middle East or northern Africa. Our analysis showed several new findings. First, all European, Middle Eastern, and African samples fall into a clade that is distinct from other contemporary Asian clades, all of which share common ancestry with the original 1997 Hong Kong strain. Phylogenetic trees built on each of the 8 segments show a consistent picture of 3 lineages, as illustrated by the HA tree shown in Figure 1. Two of the clades contain exclusively Vietnamese isolates; the smaller of these, with 5 isolates, we label V1; the larger clade, with 9 isolates, is V2. The remaining 22 isolates all fall into a third, clearly distinct clade, labeled EMA, which comprises samples from Europe, the Middle East, and Africa. Trees for the other 7 segments display a similar topology, with clades V1, V2, and EMA clearly separated in each case. Analyses of all available complete influenza (H5N1) genomes and of 589 HA sequences placed the EMA clade as distinct from the major clades circulating in People's Republic of China, Indonesia, and Southeast Asia." [23]
See https://web.archive.org/web/20090709040039/http://who.int/csr/disease/avian_influenza/H5CompleteTree.pdf for a Genetic Tree of 1,342 H5N1 viruses based on their HA gene, showing their clade designations.
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.
Avian influenza, also known as avian flu, is a bird flu caused by the influenza A virus, which can infect people. It is similar to other types of animal flu in that it is caused by a virus strain that has adapted to a specific host. The type with the greatest risk is highly pathogenic avian influenza (HPAI).
Antigenic shift is the process by which two or more different strains of a virus, or strains 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. Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change.
Influenza hemagglutinin (HA) or haemagglutinin[p] is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.
Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).
Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.
Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus which can cause illness in humans and many other species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of type A of subtype H5N1, is the highly pathogenic causative agent of H5N1 flu, commonly known as avian influenza. It is enzootic in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic and panzootic, killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. Many references to "bird flu" and H5N1 in the popular media refer to this strain.
Transmission and infection of H5N1 from infected avian sources to humans has been a concern since the first documented case of human infection in 1997, due to the global spread of H5N1 that constitutes a pandemic threat.
Influenza A virus subtype H9N2 (A/H9N2) is a subtype of the species Influenza A virus . Since 1998 a total of 86 cases of human infection with H9N2 viruses have been reported.
Spanish flu research concerns studies regarding the causes and characteristics of the Spanish flu, a variety of influenza that in 1918 was responsible for the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in the literature, but it was not until 2005, when various samples of lung tissue were recovered from American World War I soldiers and from an Inupiat woman buried in permafrost in a mass grave in Brevig Mission, Alaska, that significant genetic research was made possible.
The NS1 influenza protein (NS1) is a viral nonstructural protein encoded by the NS gene segments of type A, B and C influenza viruses. Also encoded by this segment is the nuclear export protein (NEP), formally referred to as NS2 protein, which mediates the export of influenza virus ribonucleoprotein (RNP) complexes from the nucleus, where they are assembled.
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, making it one of the mechanisms of antigenic escape. 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.
Fujian flu refers to flu caused by either a Fujian human flu strain of the H3N2 subtype of the Influenza A virus or a Fujian bird flu strain of the H5N1 subtype of the Influenza A virus. These strains are named after Fujian, a coastal province in Southeast China.
The Goose Guangdong virus refers to the strain A/Goose/Guangdong/1/96 (Gs/Gd)-like H5N1 HPAI viruses. It is a strain of the Influenzavirus A subtype H5N1 virus that was first detected in a goose in Guangdong in 1996. It is an HPAI virus, meaning that it can kill a very high percentage of chickens in a flock in mere days. It is believed to be the immediate precursor of the current dominant strain of HPAI A(H5N1) that evolved from 1999 to 2002 creating the Z genotype that is spreading globally and is epizootic and panzootic, killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread.
Human mortality from H5N1 or the human fatality ratio from H5N1 or the case-fatality rate of H5N1 is the ratio of the number of confirmed human deaths resulting from confirmed cases of transmission and infection of H5N1 to the number of those confirmed cases. For example, if there are 100 confirmed cases of humans infected with H5N1 and 10 die, then there is a 10% human fatality ratio. H5N1 flu is a concern due to the global spread of H5N1 that constitutes a pandemic threat. The majority of H5N1 flu cases have been reported in southeast and east Asia. The case-fatality rate is central to pandemic planning. Estimates of case-fatality (CF) rates for past influenza pandemics have ranged from to 2-3% for the 1918 pandemic to about 0.6% for the 1957 pandemic to 0.2% for the 1968 pandemic. As of 2008, the official World Health Organization estimate for the case-fatality rate for the outbreak of H5N1 avian influenza was approximately 60%. Public health officials in Ontario, Canada argue that the true case-fatality rate could be lower, pointing to studies suggesting it could be 14-33%, and warned that it was unlikely to be as low as the 0.1–0.4% rate that was built into many pandemic plans.
Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus and last for about 2–8 days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.
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. Viral neuraminidase was discovered by Alfred Gottschalk at the Walter and Eliza Hall Institute in 1957. Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza.
The pandemic H1N1/09 virus is a swine origin influenza A virus subtype H1N1 strain that was responsible for the 2009 swine flu pandemic. This strain is often called swine flu by the public media. For other names, see the Nomenclature section below.
A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1.
In parasitology and epidemiology, a host switch is an evolutionary change of the host specificity of a parasite or pathogen. For example, the human immunodeficiency virus used to infect and circulate in non-human primates in West-central Africa, but switched to humans in the early 20th century.
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