H5N1 genetic structure

Encyclopedia : H : H5 : H5N : H5N1 genetic structure

Flu und legende color c.jpg

H5N1

Influenza A virus subtype H5N1
Genetic structure
Infection
Global spread
Social impact
Pandemic
WHO pandemic phases
1. Low risk
2. New virus
3. Self limiting
4. Person to person
5. Epidemic exists
6. Pandemic exists
"H5N1 genetic structure" refers to the molecular structure of the H5N1 virus's RNA.

**H5N1**
Influenza A virus subtype H5N1 Genetic structure Infection Global spread Social impact Pandemic
WHO pandemic phases 1. Low risk 2. New virus 3. Self limiting 4. Person to person 5. Epidemic exists 6. Pandemic exists

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 [Evolution of H5N1 viruses in Asia] by The World Health Organization Global Influenza Program Surveillance Network in Emerging Infectious Diseases (2005). See [Figure 1] for a diagramatic representation of the genetic relatedness of Asian H5N1 hemagglutinin genes from various isolates of the virus. 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. PDF format: [H5N1 avian influenza: timeline] from the World Health Organization (dated October 28, 2005). 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 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.

Contents

1 Terminology
2 Context
3 Surface encoding gene segments
4 Internal encoding gene segments

4.1 Matrix encoding gene segments
4.2 Nucleoprotein encoding gene segments
4.3 Polymerase encoding gene segments

5 Mutation
6 See also
7 Sources
8 Further reading

Terminology

The Orthomyxovirus family consists of 5 genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, and Thogotovirus.

The "RNA viruses" includes the "negative-sense ssRNA viruses" which includes the Order "Mononegavirales" which includes 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" and 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 is about 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

Virus

A virus is one type of microscopic parasite that infects cells in biological organisms.

Orthomyxoviridae

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

"Influenza virus" refers to a subset of Orthomyxoviridae that create influenza. This is not a phylogenetics based taxonomic category.

Influenza A virus

Influenza A viruses have 10 genes on eight separate RNA molecules (called: 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. [Nature] article A novel influenza A virus mitochondrial protein that induces cell death Nature Medicine 7, 1306 - 1312 (2001) doi:10.1038/nm1201-1306 ) 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 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." [Definition of the minimal viral components required for the initiation of unprimed RNA synthesis by influenza virus RNA polymerase] Nucleic Acids Research 2002 January 15; 30(2): 429–438.

Surface encoding gene segments

Surface antigen encoding gene segments (RNA molecule): (HA, NA)
*HA 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." [Greninger Paper (PDF)] A mutation found in Turkey in 2006 "involves a substitution in one sample of an amino acid at position 223 of the haemoagglutinin 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 Kong in 2003, and in one fatal case in Vietnam 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. [Nature magazine article "Alarms ring over bird flu mutations"] January 2006 "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."[H5N1 influenza: A protean pandemic threat] Recent research reveals that humans have avian type receptors at very low densities and chickens have human type receptors at very low densities. [Influenza Report 2006] Online book page 51

*NA codes for neuraminidase which is an antigenic glycoprotein enzyme found on the surface of the influenza viruses. It helps the release of progeny viruses from infected cells.

Internal encoding gene segments

Internal viral protein encoding gene segments (RNA molecule): (M, NP, NS, PA, PB1, PB2) [The Threat of Pandemic Influenza: Are We Ready? Page 118]

Matrix encoding gene segments

*M codes for the matrix proteins (M1 and M2) that along with the two surface proteins (hemagglutinin and neuraminidase) make up the capsid (protective coat) of the virus. It encodes by using different reading frames from the same RNA segment.
**M1 is a protein that binds to the viral RNA.
**M2 is a protein that uncoats the virus exposing its contents (the eight RNA segments) to the cytoplasm of the host cell. The M2 transmembrane protein is an ion channel required for efficient infection. [Influenza virus replication] in Medical Microbiology, 4th edition edited by Samuel Baron. 1996 Chapter 58. ISBN 0963117211. The amino acid substitution (Ser31Asn) in M2 some H5N1 genotypes is associated with amantadine resistance. [H5N1 influenza: A protean pandemic threat] National Academy of Sciences | PNAS | May 25, 2004 | vol. 101 | no. 21 | 8156-8161

Nucleoprotein encoding gene segments

*NP codes for nucleoprotein.
*NS: NS codes for two nonstructural proteins (NS1 and NEP). "[T]he pathogenicity of influenza virus was related to the nonstructural (NS) gene of the H5N1/97 virus" [Characterization of Highly Pathogenic H5N1 Avian Influenza A Viruses Isolated from South Korea] Journal of Virology, March 2005, p. 3692-3702, Vol. 79, No. 6. Also, [Pandemic Influenza] Center for Infectious Disease Research & Policy Academic Health Center -- University of Minnesota
**NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. NS1 described in. [Inhibition by the NS1 protein - Enhanced virulence/viral pathogenesis by enabling the virus to disarm the host cell type IFN defense system] Pathobiologics International 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 response (especially TNFa) induced by these viruses in human macrophages" [CDC volume 12 number 1]. 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." [The Definition and Measurement of Dangerous Research by Alex Greninger]
**NEP: The "nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPs" [Influenza B and C Virus NEP (NS2) Proteins Possess Nuclear Export Activities] Journal of Virology, August 2001, p. 7375-7383, Vol. 75, No. 16

Polymerase encoding gene segments

*PA codes for the PA protein which is a critical component of the viral polymerase.
*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 [A novel influenza A virus mitochondrial protein that induces cell death] Nature Medicine 7, 1306 - 1312 (2001) doi:10.1038/nm1201-1306.
*PB2 codes for the PB2 protein which is a critical component of the viral polymerase. 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. [The Threat of Pandemic Influenza: Are We Ready? Page 126] Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine.

Mutation

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species. [New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China] by Z. Kou, F. M. Lei, J. Yu, Z. J. Fan, Z. H. Yin, C. X. Jia, K. J. Xiong, Y. H. Sun, X. W. Zhang, X. M. Wu, X. B. Gao and T. X. Li in Journal of Virology (2005) volume 79, pages 15460-15466. 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. [Evolution of the receptor binding phenotype of influenza A (H5) viruses] by A. Gambaryan, A. Tuzikov, G. Pazynina, N. Bovin, A. Balish and A. Klimov in Virology (2005) electronic release on October 11 ahead of print publication. This doesn't mean one amino acid substitution can cause a pandemic but it does mean one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans.

In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Professor Robert 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". [The evolution of H5N1 influenza viruses in ducks in southern China] by H. Chen, G. Deng, Z. Li, G. Tian, Y. Li, P. Jiao, L. Zhang, Z. Liu, R. G. Webster and K. Yu in Proceedings of the National Academy of Sciences of the United States of America (2004) volume 101, pages 10452-10457. Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.