H5N1: Meaning (information, definition, explanation, facts)

H5N1 is an avian influenza virus subtype. The H5N1 flu is what is commonly meant when speaking of "bird flu" or "avian influenza". It is a viral disease that causes illness in many species including humans and is a pandemic threat. 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 is widespread in the bird population. It is very easy for birds to catch avian flu from each other. Most humans known to have become infected had a lot of physical contact with infected birds, or, rarely, an infected relative. While H5N1 is mutating into variations which infect species not previously known to carry the virus, not all of these variations can infect humans.

A highly pathogenic variation of H5N1 is currently spreading across the world from areas where it is endemic. Migrating waterfowl (wild ducks, geese, and swans) carry H5N1, often without themselves becoming sick. ^{[#endnote_waterfowl][#endnote_swans]} Avian flu is also spread through domestic poultry, both through movements of infected birds and poultry products, and the use of infected poultry manure as fertiliser or feed. Humans with H5N1 have typically caught it from chickens, which were in turn infected by other poultry or waterfowl.

H5N1 is currently endemic in birds in southeast Asia and is threatening to become endemic in birds everywhere else. Tens of millions of birds have died of H5N1 influenza and hundreds of millions of birds have been slaughtered and disposed of to try to control the spread of the disease ^[2].

Not all cases of human H5N1 infection are reported and consequently the exact mortality rate is unknown. Earlier historical flu pandemics, which were also believed to be of avian origin, had reportedly an average mortality rate of 2.5-5%. The current projected worst case scenario for a H5N1 pandemic is somewhere around 150 million human deaths directly due to H5N1 infection (or two to three percent of the world's human population). No one knows what the chances are for this worst case scenario.

Avian Flu

Main articles: Avian influenza & Avian influenza virus

H5N1 is a subtype of the species called avian influenza virus (bird flu). Avian flu is a disease and avian flu virus is a species. The avian flu virus subtypes are labeled according to an H number and an N number.

The avian influenza subtypes that have been confirmed in humans, ordered by the number of known human deaths, are: H1N1 caused "Spanish Flu", H2N2 caused "Asian Flu", H3N2 caused "Hong Kong Flu", H5N1 is the current pandemic threat, H7N7 has unusual zoonotic potential, H1N2 is currently endemic in humans and pigs, H9N2, H7N2, H7N3, H10N7.

The annual flu (also called "seasonal flu" or "human flu") kills an estimated 36,000 people in the United States each year. The dominant strain of annual flu virus in January 2006 was H3N2 which is now resistant to the standard antiviral drugs amantadine and rimantadine.

Avian influenza virus H3N2 is endemic in pigs ("swine flu") in China and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. Human influenza viruses can reassort with H5N1 in pigs and mutate into a form which can pass easily among humans. This is one of many possible paths to a pandemic.

Main article: Transmission and infection of H5N1

Infected birds pass on H5N1 through their saliva, nasal secretions, and feces. Other birds may pick up the virus through direct contact with these excretions or when they have contact with surfaces contaminated with this material. Because migratory birds are among the carriers of the H5N1 virus it may spread to all parts of the world. Past outbreaks of avian flu have often originated in crowded conditions in southeast and east Asia, where humans, pigs, and poultry live in close quarters. In these conditions a virus can mutate into a form that more easily infects humans.

The current method of prevention in animal populations is to destroy infected animals, as well as animals suspected of being infected. In southeast Asia, millions of domestic birds have been slaughtered to prevent the spread of the virus.

Since H5N1 is an influenza virus, symptoms similar to those of the common flu, such as fever, cough, sore throat, and sore muscles, can develop in infected humans. However, in more severe cases, pneumonia and respiratory failure can develop and eventually cause death. Patients with H5N1 avian influenza have rarely had conjunctivitis^[9], unlike human cases of infection by the H7 viruses. Severe infection from H5N1 caused multiple lung infections (including pus, fever, cough), lung scar tissue, fluid in the space surrounding the lungs, enlarged lymph nodes and cavities forming in the lung tissue.

Neuraminidase inhibitors are a class of drugs that includes zanamivir and oseltamivir, the latter being licensed for prophylaxis treatment in the United Kingdom. Oseltamivir inhibits the influenza virus from spreading inside the user's body ^[8]. It is marketed by Roche as Tamiflu. This drug has become a focus for some governments and organizations trying to be seen as making preparations for a possible H5N1 pandemic. In August 2005, Roche agreed to donate three million courses of Tamiflu to the World Health Organization, to be deployed by the WHO to contain a pandemic in its region of origin. Although Tamiflu is patented, international law gives governments wide freedom to issue compulsory licenses for life-saving drugs.

Main article: Global spread of H5N1

"Since 1997, studies of influenza A (H5N1) indicate that these viruses continue to evolve, with changes in antigenicity and internal gene constellations; an expanded host range in avian species and the ability to infect felids; enhanced pathogenicity in experimentally infected mice and ferrets, in which they cause systemic infections; and increased environmental stability."^{[#endnote_Global_Spread]}

gfgfgilku

Main article: Influenza pandemic

"The United States is collaborating closely with eight international organizations, including the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE), and 88 foreign governments to address the situation through planning, greater monitoring, and full transparency in reporting and investigating avian influenza occurrences. The United States and these international partners have led global efforts to encourage countries to heighten surveillance for outbreaks in poultry and significant numbers of deaths in migratory birds and to rapidly introduce containment measures. The U.S. Agency for International Development (USAID) and the U.S. Department of State, the U.S. Department of Health and Human Services (HHS), and Agriculture (USDA) are coordinating future international response measures on behalf of the White House with departments and agencies across the federal government." ^{[#endnote_usaid.gov]}

Together steps are being taken to "minimize the risk of further spread in animal populations", "reduce the risk of human infections", and "further support pandemic planning and preparedness".^{[#endnote_usaid.gov]}

Ongoing detailed mutually coordinated onsite surveillance and analysis of human and animal H5N1 avian flu outbreaks are being conducted and reported by the USGS National Wildlife Health Center, the Centers for Disease Control and Prevention, the World Health Organization, the European Commission, and others.^{[#endnote_outbreaks]}

H5N1 is a type of avian influenza virus (bird flu virus) that has mutated^{[#endnote_CDCWHO]} 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^{[#endnote_workshop]} that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans^{[#endnote_timeline]}. 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 avian influenza virus H5N1 is now the dominant genotype of H5N1. Genotype Z is endemic in birds in southeast Asia and represents a long term pandemic threat.

The species called the avian flu virus has a subtype called H5N1 which has a strain called highly pathogenic H5N1 which includes genotype or strain Z which has been divided into two genetic clades which are known from specific isolates. Among H5N1 viruses, only clade one infects humans.

Terminology

"Virus" refers to either the complete virus assemblage or when distinguishing between its parts it refers to the molecules (RNA in the case of H5N1) comprising the genome that is surrounded (encapsidated) by a protective coat of protein called a capsid which binds directly to the viral genome. This complex of protein and nucleic acid is called the nucleocapsid. The complete virus assemblage is referred to as a virion. In normal useage "H5N1 virus" refers to the H5N1 nucleocapsid which is the same as the H5N1 virion since the H5N1 lacks an envelope (a membranous lipid structure that surrounds the nucleocapsid).

Avian influenza is not a genus of Orthomyxoviridae. The term "avian influenza" denotes a disease not a virus. The orthomyxovirus family consists of 5 genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, and Thogotovirus. Influenzavirus A is not the same as "avian influenza": the former is a genus of viruses, the latter is an illness.

In phylogenetics based taxonomy 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 (or "type species") called "Influenza A virus" (AI) 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 distiction 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.

The species called the avian flu virus has a subtype called H5N1 which has a strain called highly pathogenic H5N1 which includes genotype or strain Z which has been divided into two genetic clades which are known from specific isolates. Only clade one infects humans but all clade one are resistant to adamantanes. Each specific known genetic variation is known from a virus isolate of a specific case of infection.^{[#endnote_Terminology]}

Influenza virus isolates are notated as in this example: A/New York/348(H1N2):

• A stands for the species of influenza (A, B, or C).
• New York is the place this specific virus was isolated.
• 348 is the number of the specimen it was isolated from.
• H1 stands for the first of several known types of the protein hemagglutinin.
• N2 stands for the second of several known types of the protein neuraminidase.

H5N1 virus structure

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.

Avian influenza virus

Avian influenza 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. 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]. Avian influenza viruses compose the Influenzavirus A genus of the Orthomyxoviridae family and are negative sense, single-stranded, segmented RNA viruses.

"The influenza virus RNA polymerase is a mulzhjhjkhtifunctional 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."^{[#endnote_structure2]}

• 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."^{[#endnote_structure3]} 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. ^{[#endnote_nature_jan_2006]}
  • 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 viral protein encoding gene segments (RNA molecule): (M, NP, NS, PA, PB1, PB2)^{[#endnote_structure4]}
  • 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 ^{[#endnote_mechanisms]}. The amino acid substitution (Ser31Asn) in M2 some H5N1 genotypes is associated with amantadine resistance^{[#endnote_structure5]}.
  • 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"^{[#endnote_structure6][#endnote_structure7]}
    • NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. NS1 described in ^{[#endnote_structure8 detail]}. 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"^{[#endnote_structure9]}. 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."^{[#endnote_structure10]}
    • NEP: The "nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPs" ^{[#endnote_structure11]}
  • 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."^{[#endnote_structure9]} This was discovered by Chen et. al. and reported in Nature^{[#endnote_structure13]}.
  • 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.^{[#endnote_structure14][#endnote_structure6]} Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine.

The hemagglutinin, neuraminidase, and M2 proteins are essential viral proteins with functions that can be inhibited by antiviral drugs such as oseltamivir and rimantadine or bound by virus-inactivating antibodies produced by the immune system.

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^{[#endnote_variants]}. 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^{[#endnote_specificity]}. 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"^{[#endnote_ducks]}. Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

Recent research of Taubenberger et al ^{[#endnote_Taubenberger]} has shown that the 1918 virus, like H5N1, was also an avian influenza virus. Furthermore, Tumpey and colleagues ^{[#endnote_Tumpey]} who reconstructed the H1N1 virus of 1918 came to the conclusion that it is was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Human forms of seven of the ten amino acids have already been identified in currently circulating H5N1. It is not unlikely that the other mutations eventually will surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918.

1. ^ Wild birds and Avian Influenza An example : "In Russia and Kazakhstan, contact between domestic poultry and wild waterfowl at open water reservoirs is considered the primary source of infection for poultry."
2. ^ OIE HIGHLY PATHOGENIC AVIAN INFLUENZA IN CROATIA Follow-up report No. 4 Information received on January 19, 2006 from Dr Mate Brstilo, Director of the Veterinary Administration, Ministry of Agriculture and Forestry, Zagreb. "Source of outbreak or origin of infection: seasonal migration of wild birds - swans."
3. ^ Mutation of bird flu virus in Turkey stirs concerns by Daniel Williams and Alan Sipress, Washington Post; Reprinted in the Boston Globe, January 12 2006.
4. ^ PDF of field report by OIE on January 12, 2006 in Turkey.
5. ^ WHO facts sheet
6. ^ ^a  Full text article online: "Avian Influenza A (H5N1) Infection in Humans" by The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 in New England Journal of Medicine (September 29, 2005) Volume 353 pages 1374-1385.
7. ^ ^a  Oseltamivir (Tamiflu) information from United States National Institutes of Health. Webpage content initially developed on January 13, 2000 and revised on January 10, 2001.
8. ^  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.
9. ^ Global Spread
10. ^ ^a b  Evolution of H5N1 avian influenza 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.
11. ^ ^a  "The Threat of Pandemic Influenza: Are We Ready?" Board on Global Health Workshop Summary (2005). See page 118 for a map and page 123 for a diagram of reassortment of viral genes. The bird culls are described on page 116.
12. ^  PDF format: H5N1 avian influenza: timeline from the World Health Organization (dated October 28, 2005).
13. ^ Mortalities from a Flu Pandemic Hard to Predict by Jon Hamilton of National Public Radio Morning Edition, December 16, 2005.
14. ^  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.
15. ^  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.
16. ^  Interim Guidance about Avian Influenza A (H5N1) for U.S. Citizens Living Abroad from the U.S. Centers for Disease Control and Prevention. Initial release, March 24, 2005. Updated on November 18, 2005.
17. ^  Bird flu vaccine won't precede pandemic by Jennifer Schultz for United Press International (November 28, 2005).
18. ^  "Avian Influenza: 'Pandemic Vaccine' Appears to Protect Only at High Doses" by Martin Enserink in Science, volume 309, page 996, August 12, 2005

1. ^ Influenza: The world is teetering on the edge of a pandemic that could kill a large fraction of the human population by Robert G. Webster and Elizabeth Jane Walker in American Scientist 2003 Volume 91 Page 122.
2. ^  Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells by M. C. Chan et al in Respiratory Research 2005 Volume 6 page 135.
3. ^  Influenza virus replication in Medical Microbiology, 4th edition edited by Samuel Baron. 1996 Chapter 58. ISBN 0963117211.
4. ^ Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans By Alan Sipress in the Washington Post Saturday, June 18, 2005.
5. ^ {Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. October 6, 2005;437(7060):889-893}
6. ^ {Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solorzano A, Swayne DE, Cox NJ, Katz JM, Taubenberger JK, Palese P, Garcia-Sastre A. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science. October 7, 2005;310(5745):77-80}
7. ^ Avian Influenza activities
8. ^ Outbreaks
9. ^  NCBI APIC CDC
10. ^  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.
11. ^  Greninger Paper (PDF)
12. ^  Nature magazine article "Alarms ring over bird flu mutations" January 2006
13. ^  The Threat of Pandemic Influenza: Are We Ready? Page 118
14. ^  H5N1 influenza: A protean pandemic threat National Academy of Sciences | PNAS | May 25, 2004 | vol. 101 | no. 21 | 8156-8161
15. ^  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
16. ^  Pandemic Influenza Center for Infectious Disease Research & Policy Academic Health Center -- University of Minnesota
17. ^  Inhibition by the NS1 protein - Enhanced virulence/viral pathogenesis by enabling the virus to disarm the host cell type IFN defense system Pathobiologics International
18. ^  CDC volume 12 number 1
19. ^  The Definition and Measurement of Dangerous Research by Alex Greninger
20. ^  Influenza B and C Virus NEP (NS2) Proteins Possess Nuclear Export Activities Journal of Virology, August 2001, p. 7375-7383, Vol. 75, No. 16
21. ^  A novel influenza A virus mitochondrial protein that induces cell death Nature Medicine 7, 1306 - 1312 (2001) doi:10.1038/nm1201-1306
22. ^  The Threat of Pandemic Influenza: Are We Ready? Page 126

• Centers for Disease Control 2005. "Key Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus: May 24) )] [[2005."]
• Horimoto, T. & Kawaoka, Y. 2005. Influenza. In Nature reviews microbiology, 3, 591 – 600.
• Kuiken T et al 2004, Avian H5N1 Influenza in Cats, Science 2004 306: 241 (DOI:(_(http://dx.doi.org/10.1126/science.1102287)(10.1126/science.1102287 )

Official - international

• UN United Nations
  • WHO World Health Organization
    • The United Nation's World Health Organization's Avian Flu Facts Sheet for 2006
    • Epidemic and Pandemic Alert and Response Guide to WHO's H5N1 pages
    • Avian Influenza Resources (updated) - tracks human cases and deaths
    • National Influenza Pandemic Plans
    • WHO Collaborating Centres and Reference Laboratories Centers, names, locations, and phone numbers
  • FAO Avian Influenza portal Information resources, animations, videos, photos
    • FAO Food and Agriculture Organisation - Bi-weekly Avian Influenza Maps - tracks animal cases and deaths
    • FAO Bird Flu disease card
    • FAO Socio-Economic impact of AI Projects, Information resources
• OIE World Organisation for Animal Health - tracks animal cases and deaths
  • Official outbreak reports by country
  • Official outbreak reports by week
  • Chart of outbreaks by country

Official - United States

• PandemicFlu.Gov U.S. Government's avian flu information site
• USAID U.S. Agency for International Development - Avian Influenza Response
• CDC Centers for Disease Control - responsible agency for avian influenza in humans in US - Facts About Avian Influenza (Bird Flu) and Avian Influenza A (H5N1) Virus
• NWHC National Wildlife Health Center - responsible agency for avian influenza in animals in US
• HHS U.S. Department of Health & Human Services - Pandemic Influenza Plan

Technical

• Influenza Report 2006 Online book. Research level quality information. Highly recommended.
• Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution Nature magazine presents a summary of what has been discovered in the Influenza Genome Sequencing Project.
• 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
• Latest publications on H5N1
• Full HTML text of Avian Influenza A (H5N1) Infection in Humans by The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 in the September 29, 2005 New England Journal of Medicine
• 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 reassortment of H5N1 from 1999 to 2004 that created the Z genotype in 2002.
  • Here is the tree showing evolution by antigenic drift since 2002 that created dozens of highly pathogenic varieties of the Z genotype of avian flu virus H5N1, some of which are increasingly adopted to mammals.
• Evolutionary characterization of the six internal genes of H5N1 human influenza A virus
• Genome database Page links to the complete sequence of the Influenza A virus (A/Goose/Guangdong/1/96(H5N1)) genome.

News and General information

Please see Global spread of H5N1.