H5N1 genetic structure
Encyclopedia
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
through antigenic drift
into dozens of highly pathogen
ic varieties, but all currently belonging to genotype
Z of avian influenza virus H5N1. Genotype Z emerged through reassortment
in 2002 from earlier highly pathogen
ic genotypes of H5N1 that first appeared in China
in 1996 in bird
s and in Hong Kong
in 1997 in human
s. 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."
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 antigen
s 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 http://www.microbiologybytes.com/virology/Orthomyxoviruses.html:
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 antigen
ic glycoprotein
found on the surface of the influenza
virus
es 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
."
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." This was discovered by Chen et al. and reported in Nature
. "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."
, Influenzavirus B
, Influenzavirus C
, Isavirus, and Thogotovirus
.
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.
Virus
A virus
is one type of microscopic parasite that infects cell
s in biological organisms.
Orthomyxoviridae
The Orthomyxoviridae
are a family of RNA virus
es which infect vertebrates. It includes those virus
es which cause influenza
. Viruses of this family contain 7 to 8 segments of linear negative-sense single-stranded RNA
.
Influenza virus
"Influenza virus" refers to a subset of Orthomyxoviridae
that create influenza
. This taxonomic category is not based on phylogenetics
.
Influenza A virus
Influenza A viruses have 10 gene
s 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.) 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. Influenza A virus is the only species in the Influenzavirus A
genus
of the Orthomyxoviridae
family and are negative sense, single-stranded, segmented RNA virus
es.
"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."
es. 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 mutation
s 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. 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". This e-book is under constant revision and is an excellent guide to Avian Influenza
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". 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 antigen
ic 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."
See 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.
H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
virus's RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
.
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
H2N2
H2N2 is a subtype of the type influenzavirus A. H2N2 has mutated into various strains including the Asian flu strain , H3N2, and various strains found in birds...
when it evolved into the Hong Kong Flu
Hong Kong flu
The Hong Kong flu 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...
strain of H3N2
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
.
H5N1 has mutated
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
through antigenic drift
Antigenic drift
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 receptors, which prevent...
into dozens of highly pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
ic varieties, but all currently belonging to genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
Z of avian influenza virus H5N1. Genotype Z emerged through reassortment
Reassortment
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...
in 2002 from earlier highly pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
ic genotypes of H5N1 that first appeared in China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
in 1996 in bird
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...
s and in Hong Kong
Hong Kong
Hong Kong is one of two Special Administrative Regions of the People's Republic of China , the other being Macau. A city-state situated on China's south coast and enclosed by the Pearl River Delta and South China Sea, it is renowned for its expansive skyline and deep natural harbour...
in 1997 in human
Human
Humans are the only living species in the Homo genus...
s. 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."
This infection of humans coincided with an epizootic
Epizootic
In epizoology, an epizootic is a disease that appears as new cases in a given animal population, during a given period, at a rate that substantially exceeds what is "expected" based on recent experience . Epidemic is the analogous term applied to human populations...
(an epidemic
Epidemic
In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
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 antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s present on the virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
: hemagglutinin
Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
type 5 and neuraminidase
Neuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
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
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
molecules http://www.microbiologybytes.com/virology/Orthomyxoviruses.html:
- PB2 (polymerasePolymeraseA polymerase is an enzyme whose central function is associated with polymers of nucleic acids such as RNA and DNA.The primary function of a polymerase is the polymerization of new DNA or RNA against an existing DNA or RNA template in the processes of replication and transcription...
basic 1) - PB1 (polymerase basic 2)
- PB1-F2 (alternate open reading frame near the 5' end of the PB1 gene)
- PA (polymerase acidic)
- HA (hemagglutinin)
- NP (nucleoproteinInfluenza virus nucleoproteinInfluenza virus nucleoprotein is a structural protein which encapsidates the negative strand viral RNA. NP is one of the main determinants of species specificity. The question of how far the NP gene can cross the species barrier by reassortment and become adapted by mutation to the new host has...
) - NA (neuraminidaseViral neuraminidaseViral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell...
) - M1M1 proteinThe M1 protein is a matrix protein of the influenza virus. It forms a coat inside the viral envelope.The M1 protein binds to the viral RNA. The binding is not specific to any RNA sequence, and is performed via a peptide sequence rich in basic amino acids....
and M2M2 proteinThe M2 protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer , where the units are helices stabilized by two disulfide bonds...
(matrix) - NS1 (non-structural)
- NEP/NS2 (nuclear export of vRNPs)
Two of the most important RNA molecules are HA and PB1. HA creates a surface antigen that is especially important in transmissibility
Basic reproduction number
In epidemiology, the basic reproduction number of an infection is the mean number of secondary cases caused by an individual infected soon after disease introduction into a population with no pre-existing immunity to the disease in the absence of interventions to control...
. PB1 creates a viral polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
molecule that is especially important in virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
.
The HA RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
molecule contains the HA gene, which codes for hemagglutinin
Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
, which is an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
found on the surface of the influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es and is responsible for binding the virus to the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
that is being infected. Hemagglutinin forms spikes at the surface of flu viruses that function to attach viruses to cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. 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
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic 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
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
study that mated in a laboratory an avian flu
Avian flu
Avian influenza, sometimes avian flu, and commonly bird flu, refers to "influenza caused by viruses adapted to birds." Of the greatest concern is highly pathogenic avian influenza ....
H5N1
H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
virus that circulated in Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
in 2004 and a human flu
Human flu
Human flu is a term used to refer to influenza cases caused by Orthomyxoviridae that are endemic to human populations . It is an arbitrary categorization scheme, and is not associated with phylogenetics-based taxonomy...
H3N2
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
virus recovered in Wyoming
Wyoming
Wyoming is a state in the mountain region of the Western United States. The western two thirds of the state is covered mostly with the mountain ranges and rangelands in the foothills of the Eastern Rocky Mountains, while the eastern third of the state is high elevation prairie known as the High...
in 2003 produced 63 viruses representing various potential combinations of human and avian influenza A virus genes. One in five were lethal to mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
at low doses. The virus that most closely matched H5N1 for virulence was one with the hemagglutinin
Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
(HA), the neuraminidase
Neuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
(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
Reassortment
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...
."
PB1 codes for the PB1 protein and the PB1-F2 protein. The PB1 protein is a critical component of the viral polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
. 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. [...] PB1-F2 likely contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza." This was discovered by Chen et al. and reported in Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
. "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."
Terminology
The Orthomyxovirus family consists of 5 genera: Influenzavirus AInfluenzavirus A
Influenza A virus causes influenza in birds and some mammals and is the only species of Influenzavirus A. Influenzavirus A is a genus of the Orthomyxoviridae family of viruses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon...
, Influenzavirus B
Influenzavirus B
Influenzavirus B is a genus in the virus family Orthomyxoviridae. The only species in this genus is called "Influenza B virus".Influenza B viruses are only known to infect humans and seals, giving them influenza...
, Influenzavirus C
Influenzavirus C
Influenzavirus C is a genus in the virus family Orthomyxoviridae, which includes those viruses which cause influenza. The only species in this genus is called "Influenza C virus".Influenza C viruses are known to infect humans and pigs, giving them influenza...
, Isavirus, and Thogotovirus
Thogotovirus
Thogotovirus is a genus in the virus family Orthomyxoviridae. It can replicate in both tick cells and vertebrate cells and is usually transmitted by ticks....
.
The "RNA viruses" include the "negative-sense ssRNA viruses" which include the Family "Orthomyxoviridae" which contains five genera, classified by variations in nucleoprotein
Nucleoprotein
A nucleoprotein is any protein that is structurally associated with nucleic acid .Many viruses harness this protein, and they are known for being host-specific...
(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
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
.
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
Flock (birds)
A flock is a group of birds conducting flocking behavior in flight, or while foraging. The term is akin to the herd amongst mammals. The benefits of aggregating in flocks are varied and flocks will form explicitly for specific purposes...
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.
Context
A virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
is one type of microscopic parasite that infects cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s in biological organisms.
Orthomyxoviridae
The Orthomyxoviridae
Orthomyxoviridae
The Orthomyxoviridae are a family of RNA viruses that includes five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. A sixth has recently been described...
are a family of RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
es which infect vertebrates. It includes those virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es which cause influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
. Viruses of this family contain 7 to 8 segments of linear negative-sense single-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
.
Influenza virus
"Influenza virus" refers to a subset of Orthomyxoviridae
Orthomyxoviridae
The Orthomyxoviridae are a family of RNA viruses that includes five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. A sixth has recently been described...
that create influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
. This taxonomic category is not based on phylogenetics
Phylogenetics
In biology, phylogenetics is the study of evolutionary relatedness among groups of organisms , which is discovered through molecular sequencing data and morphological data matrices...
.
Influenza A virus
Influenza A viruses have 10 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s 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
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
. (An eleventh recently discovered gene called PB1-F2 sometimes creates a protein but is absent from some influenza virus isolates.) This segmentation of the influenza genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
facilitates genetic recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
by segment reassortment in hosts who are infected with two different influenza viruses at the same time. Influenza A virus is the only species in the Influenzavirus A
Influenzavirus A
Influenza A virus causes influenza in birds and some mammals and is the only species of Influenzavirus A. Influenzavirus A is a genus of the Orthomyxoviridae family of viruses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon...
genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
of the Orthomyxoviridae
Orthomyxoviridae
The Orthomyxoviridae are a family of RNA viruses that includes five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. A sixth has recently been described...
family and are negative sense, single-stranded, segmented RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
es.
"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."
Surface encoding gene segments
- Surface antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
encoding gene segments (RNA molecule): (HA, NA) - HA codes for hemagglutininHemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
which is an antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic glycoproteinGlycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
found on the surface of the influenzaInfluenzaInfluenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
virusVirusA virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es and is responsible for binding the virus to the cellCell (biology)The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
that is being infected. HemagglutininHemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
forms spikes at the surface of flu viruses that function to attach viruses to cellsCell (biology)The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. 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 acidSialic acidSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic 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." A mutation found in TurkeyTurkeyTurkey , known officially as the Republic of Turkey , is a Eurasian country located in Western Asia and in East Thrace in Southeastern Europe...
in 2006 "involves a substitution in one sample of an amino acid at position 223 of the haemoagglutininHemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
receptor protein. This protein allows the flu virus to bind to the receptors on the surface of its host's cells. This mutation has been observed twice before — in a father and son in Hong KongHong KongHong Kong is one of two Special Administrative Regions of the People's Republic of China , the other being Macau. A city-state situated on China's south coast and enclosed by the Pearl River Delta and South China Sea, it is renowned for its expansive skyline and deep natural harbour...
in 2003, and in one fatal case in VietnamVietnamVietnam – sometimes spelled Viet Nam , officially the Socialist Republic of Vietnam – is the easternmost country on the Indochina Peninsula in Southeast Asia. It is bordered by China to the north, Laos to the northwest, Cambodia to the southwest, and the South China Sea –...
last year. It increases the virus's ability to bind to human receptors, and decreases its affinity for poultry receptors, making strains with this mutation better adapted to infecting humans." Another mutation in the same sample at position 153 has as yet unknown effects. "Amino acid residues at positions 226 and 228 of the receptor binding pocket of HA appear to determine binding affinity to cell surface receptors and to influence the selective binding of the virus to avian (sialic acid -2,3-NeuAcGal) or human (sialic acid -2,6-NeuAcGal) cell surface receptors. The human A/HK/212/03 and A/HK/213/03 isolates retain the signature associated with avian receptor binding, but they have a unique amino acid substitution (Ser227Ile) within the receptor binding pocket that was not present even in the closely related A/Gs/HK/739.2/02 (genotype Z+) virus." Recent research reveals that humans have avian type receptors at very low densities and chickens have human type receptors at very low densities. Researchers "found that the mutations at two places in the gene, identified as 182 and 192, allow the virus to bind to both bird and human receptors." See research articles Host Range Restriction and Pathogenicity in the Context of Influenza Pandemic (Centers for Disease Control and Prevention, 2006) (by Gabriele Neumann and Yoshihiro Kawaoka) and Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus (American Association for the Advancement of Science, 2006) (by James Stevens, Ola Blixt, Terrence M. Tumpey, Jeffery K. Taubenberger, James C. Paulson, Ian A. Wilson) for further details.
- NA codes for neuraminidaseNeuraminidaseNeuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
which is an antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic glycoproteinGlycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
found on the surface of the influenzaInfluenzaInfluenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
virusVirusA virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es. It helps the release of progeny viruses from infected cells. Flu drugs Tamiflu and Relenza work by inhibiting some strains of neuraminidaseNeuraminidaseNeuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
. They were developed based on N2 and N9. "In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins. [...] When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins."
Internal encoding gene segments
- Internal viral protein encoding gene segments (RNA molecule): (M, NP, NS, PA, PB1, PB2)
Matrix encoding gene segments
- M codes for the matrix proteins (M1 and M2) that, along with the two surface proteins (hemagglutininHemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
and neuraminidaseNeuraminidaseNeuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
), make up the capsidCapsidA capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
(protective coat) of the virus. It encodes by using different reading frames from the same RNA segment.- M1M1 proteinThe M1 protein is a matrix protein of the influenza virus. It forms a coat inside the viral envelope.The M1 protein binds to the viral RNA. The binding is not specific to any RNA sequence, and is performed via a peptide sequence rich in basic amino acids....
is a protein that binds to the viral RNA. - M2M2 proteinThe M2 protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer , where the units are helices stabilized by two disulfide bonds...
is a protein that uncoats the virus, thereby exposing its contents (the eight RNA segments) to the cytoplasm of the host cell. The M2 transmembrane proteinTransmembrane proteinA transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
is an ion channelIon channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
required for efficient infection. The amino acid substitution (Ser31Asn) in M2 some H5N1 genotypes is associated with amantadine resistance.
- M1
Nucleoprotein encoding gene segments
- NP codes for nucleoproteinNucleoproteinA nucleoprotein is any protein that is structurally associated with nucleic acid .Many viruses harness this protein, and they are known for being host-specific...
. - NS: NS codes for two nonstructural proteins (NS1 and NS2 - formerly called NEP). "[T]he pathogenicity of influenza virus was related to the nonstructural (NS) gene of the H5N1/97 virus".
- NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. The "NS1 of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia might be responsible for an enhanced proinflammatory cytokineCytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
response (especially TNFa) induced by these viruses in human macrophageMacrophageMacrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s". H5N1 NS1 is characterized by a single amino acid change at position 92. By changing the amino acid from glutamic acid to aspartic acid, the researchers were able to abrogate the effect of the H5N1 NS1. [This] single amino acid change in the NS1 gene greatly increased the pathogenicity of the H5N1 influenza virus." - NEP: The "nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPRibonucleoproteinRibonucleoprotein is a nucleoprotein that contains RNA, i.e. it is an association that combines ribonucleic acid and protein together. A few known examples include the ribosome, the enzyme telomerase, vault ribonucleoproteins, and small nuclear RNPs , which are implicated in pre-mRNA splicing and...
s".
- NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. The "NS1 of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia might be responsible for an enhanced proinflammatory cytokine
Polymerase encoding gene segments
- PA codes for the PA protein which is a critical component of the viral polymeraseRNA polymeraseRNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
. - PB1 codes for the PB1 protein and the PB1-F2 protein.
- The PB1 protein is a critical component of the viral polymeraseRNA polymeraseRNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
. - 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 apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. [...] PB1-F2 likely contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza." This was discovered by Chen et al. and reported in NatureNature (journal)Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
. "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."
- The PB1 protein is a critical component of the viral polymerase
- PB2 codes for the PB2 protein which is a critical component of the viral polymeraseRNA polymeraseRNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
. As of 2005, 75% of H5N1 human virus isolates from Vietnam had a mutation consisting of Lysine at residue 627 in the PB2 protein; which is believed to cause high levels of virulence. Until H5N1, all known avian influenza viruses had a GluGlutamic acidGlutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
at position 627, while all human influenza viruses had a lysineLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
. As of 2007, "The emergence of 3 (or more) substrains from the EMA [EMA=Europe, Middle East, Africa] clade represents multiple new opportunities for avian influenza (H5N1) to evolve into a human pandemic strain. In contrast to strains circulating in Southeast Asia, EMA viruses are derived from a progenitor that has the PB2 627K mutation. These viruses are expected to have enhanced replication characteristics in mammals, and indeed the spread of EMA has coincided with the rapid appearance of cases in mammals—including humans in Turkey, Egypt, Iraq, and Djibouti, and cats in Germany, Austria, and Iraq. Unfortunately, the EMA-type viruses appear to be as virulent as the exclusively Asian strains: of 34 human infections outside of Asia through mid-2006, 15 have been fatal." Lys at PB2–627 is believed to confer to avian H5N1 viruses the advantage of efficient growth in the upper and lower respiratory tracts of mammals.
Mutation
Influenza viruses have a relatively high mutation rate that is characteristic of RNA virusRNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
es. The segmentation of the influenza genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
facilitates genetic recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
by segment reassortment in hosts who are infected with two different influenza viruses at the same time. H5N1 viruses can reassort
Reassortment
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...
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
Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
genes. Genetic mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the hemagglutinin gene that cause single amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
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. 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
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
("swine flu
Swine flu
Swine influenza, also called pig influenza, swine flu, hog flu and pig flu, is an infection by any one of several types of swine influenza virus. Swine influenza virus or S-OIV is any strain of the influenza family of viruses that is endemic in pigs...
") 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
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
, which is now resistant to the standard antiviral drugs amantadine
Amantadine
Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
and rimantadine
Rimantadine
Rimantadine is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug...
. 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
H2N2
H2N2 is a subtype of the type influenzavirus A. H2N2 has mutated into various strains including the Asian flu strain , H3N2, and various strains found in birds...
did when it evolved into the Hong Kong Flu strain of H3N2
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
.
Both the H2N2
H2N2
H2N2 is a subtype of the type influenzavirus A. H2N2 has mutated into various strains including the Asian flu strain , H3N2, and various strains found in birds...
and H3N2
H3N2
Influenza A virus subtype H3N2 is a subtype of viruses that cause influenza . H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains...
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". This e-book is under constant revision and is an excellent guide to Avian Influenza
In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin
Harbin
Harbin ; Manchu language: , Harbin; Russian: Харби́н Kharbin ), is the capital and largest city of Heilongjiang Province in Northeast China, lying on the southern bank of the Songhua River...
, China and Professor Robert G. Webster of the St Jude Children's Research Hospital, Memphis, Tennessee
Memphis, Tennessee
Memphis is a city in the southwestern corner of the U.S. state of Tennessee, and the county seat of Shelby County. The city is located on the 4th Chickasaw Bluff, south of the confluence of the Wolf and Mississippi rivers....
, reported results of experiments in which mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
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". 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 antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic clades. "Clade 1 includes human and bird isolates from Vietnam
Vietnam
Vietnam – sometimes spelled Viet Nam , officially the Socialist Republic of Vietnam – is the easternmost country on the Indochina Peninsula in Southeast Asia. It is bordered by China to the north, Laos to the northwest, Cambodia to the southwest, and the South China Sea –...
, Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
, and Cambodia
Cambodia
Cambodia , officially known as the Kingdom of Cambodia, is a country located in the southern portion of the Indochina Peninsula in Southeast Asia...
and bird isolates from Laos
Laos
Laos Lao: ສາທາລະນະລັດ ປະຊາທິປະໄຕ ປະຊາຊົນລາວ Sathalanalat Paxathipatai Paxaxon Lao, officially the Lao People's Democratic Republic, is a landlocked country in Southeast Asia, bordered by Burma and China to the northwest, Vietnam to the east, Cambodia to the south and Thailand to the west...
and Malaysia. Clade 2 viruses were first identified in bird isolates from China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
, Indonesia
Indonesia
Indonesia , officially the Republic of Indonesia , is a country in Southeast Asia and Oceania. Indonesia is an archipelago comprising approximately 13,000 islands. It has 33 provinces with over 238 million people, and is the world's fourth most populous country. Indonesia is a republic, with an...
, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, and South Korea
South Korea
The Republic of Korea , , is a sovereign state in East Asia, located on the southern portion of the Korean Peninsula. It is neighbored by the People's Republic of China to the west, Japan to the east, North Korea to the north, and the East China Sea and Republic of China to the south...
before spreading westward to the Middle East
Middle East
The Middle East is a region that encompasses Western Asia and Northern Africa. It is often used as a synonym for Near East, in opposition to Far East...
, Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
, and Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
. 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
- Subclade 1, Indonesia
- Subclade 2, Europe, Middle East, and Africa (called EMA)
- Subclade 3, China"
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."
See 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.
Further reading
- Influenza Report 2006 Online book. presents a summary of what has been discovered in the Influenza Genome Sequencing ProjectInfluenza Genome Sequencing ProjectThe Influenza Genome Sequencing Project is an American-based genome project aimed at improving the availability of genomic sequence data from influenza viruses and related information....
. - Links and descriptions to abstracts and full texts This bibliography of avian influenza publications was complied through the cooperative effort of the USGS National Wildlife Health Center and the Wildlife Disease Information Node.
- Search for research publications about H5N1: Entez PubMed
- Evolutionary "Tree of Life" for H5N1:
- Here is the phylogenetic tree of the influenza virus hemagglutinin gene segment. Amino acid changes in three lineages (bird, pig, human) of the influenza virus hemagglutinin protein segment HA1.
- Here is the tree showing the evolution by reassortmentReassortmentReassortment 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...
of H5N1 from 1999 to 2004 that created the Z genotype in 2002. - Here is the tree showing evolution by antigenic driftAntigenic driftThe 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 receptors, which prevent...
since 2002 that created dozens of highly pathogenic varieties of the Z genotype of avian flu virus H5N1, some of which are increasingly adapted to mammals. - WHO (PDF) contains latest Evolutionary "Tree of Life" for H5N1 article Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines published August 18, 2006
- Genome database Page links to the complete sequence of the Influenza A virus (A/Goose/Guangdong/1/96(H5N1)) genome.
External links
- Influenza Research Database – Database of influenza genomic sequences and related information.