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Influenza A virus subtype H5N1

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H5N1 is an avian virus which is an influenza virus. It is a pandemic threat.

Nontechnical introduction

H5N1 is sometimes called bird flu or avian influenza. It is a viral disease that causes illness in many species including humans.

As of January 5, 2006, 144 cases of infections in humans, resulting in 76 deaths, have been confirmed worldwide. Not all cases of H5N1 infection are reported, so the percent of reported deaths per reported infection is known, but the similar number for unreported cases is unknown. Thirteen countries across Asia and Europe have been affected. Tens of millions of birds died of H5N1 influenza and hundreds of millions of birds were culled (slaughtered) to protect humans from H5N1[2].

The current projected worst case scenario for a H5N1 pandemic is somewhere around 150,000,000 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.

Technical introduction

H5N1 is a type of avian influenza virus (bird flu virus) that has mutated[1] through antigenic drift into dozens of highly pathogenic varieties, but all currently belonging to genotype Z of avian influenza virus H5N1. Genotype Z emerged through reassortment in 2002 from earlier highly pathogenic genotypes of H5N1[2] that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans[3]. 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.

Influenza A virus, the virus that causes Avian flu. Transmission electron micrograph of negatively stained virus particles in late passage. (Source: Dr. Erskine Palmer, Centers for Disease Control and Prevention Public Health Image Library).
File:H5N1.JPG
Colorized transmission electron micrograph of H5N1 (golden) grown in Madin-Darby canine kidney cells (green). (Source: C. Goldsmith, J. Katz and S. Zaki. Centers for Disease Control & Prevention Public Health Image Library. Image #1841.).

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 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. [4] [5] [6]

H5N1 virus structure

See also Virus, Orthomyxoviridae, Influenza virus, Avian influenza virus
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 (also known as bird flu, avian flu, influenza virus A flu, type A flu, or genus A flu) is a flu due to a type of influenza virus that is hosted by birds, but may infect several species of mammals. The avian influenzavirus 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, H7N7, H9N2, H7N2, H7N3.

Avian influenza viruses have 10 genes on eight separate RNA molecules (called: PB2, PB1, PA, HA, NP, NA, M, and NS). (Table of molecular weights, nucleotide lengths, molecules per virion here ) 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 multifunctional complex composed of the three viral proteins PB1, PB2 and PA, which, together with the viral nucleoprotein NP, form the minimum complement required for viral mRNA synthesis and replication." [7]

  • 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.
  • Internal viral protein encoding gene segments (RNA molecule): (M, NP, NS, PA, PB1, PB2) [8]
    • 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 [9]. The amino acid substitution (Ser31Asn) in M2 some H5N1 genotypes is associated with amantadine resistance [10].
    • 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" [11] [12]
      • NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. NS1 described in detail here. 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" [13].
      • NEP: The "nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPs" [14].
    • 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-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." [15] This was discovered by Chen et. al. and reported in Nature here in 2001.
    • 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. [16] [17]

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 pathogentic to one species but not others, some pathogenic to multiple species[18]. 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[19]. 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"[20]. 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 [21] has shown that the 1918 virus, like H5N1, was also an avian influenza virus. Furthermore, Tumpey and colleagues [22] 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.

Transmission and infection

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 virus. 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.

Global spread

Main article: Global spread of H5N1
Bird Flu Spread on October 26th, 2005

"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." [23]

Confirmed human cases and mortality rate of avian influenza (H5N1) 2003–2024
Country
 Australia
 Azerbaijan
 Bangladesh
 Cambodia
 Canada
 Chile
 China
 Djibouti
 Ecuador
 Egypt
 India
 Indonesia
 Iraq
 Laos
 Myanmar
 Nepal
 Nigeria
 Pakistan
 Spain
 Thailand
 Turkey
 United Kingdom
 United States
 Vietnam
Total
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 Total
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
cases
deaths
CFR
1 0 0% 1 0 0%
8 5 62.5% 8 5 62.5%
1 0 0% 2 0 0% 3 0 0% 1 1 100% 1 0 0% 8 1 12.5%
4 4 100% 2 2 100% 1 1 100% 1 0 0% 1 0 0% 1 1 100% 8 8 100% 3 3 100% 26 14 53.8% 9 4 44.4% 6 4 66.7% 10 2 20.0% 72 43 59.7%
1 1 100% 1 1 100%
1 0 0% 1 0 0%
1 1 100% 8 5 62.5% 13 8 61.5% 5 3 60.0% 4 4 100% 7 4 57.1% 2 1 50.0% 1 1 100% 2 1 50.0% 2 2 100% 2 0 0% 6 1 16.7% 1 1 100% 1 0 0% 55 32 58.2%
1 0 0% 1 0 0%
1 0 0% 1 0 0%
18 10 55.6% 25 9 36.0% 8 4 50.0% 39 4 10.3% 29 13 44.8% 39 15 38.5% 11 5 45.5% 4 3 75.0% 37 14 37.8% 136 39 28.7% 10 3 30.0% 3 1 33.3% 359 120 33.4%
1 1 100% 1 1 100%
20 13 65.0% 55 45 81.8% 42 37 88.1% 24 20 83.3% 21 19 90.5% 9 7 77.8% 12 10 83.3% 9 9 100% 3 3 100% 2 2 100% 2 2 100% 1 1 100% 200 168 84.0%
3 2 66.6% 3 2 66.6%
2 2 100% 1 0 0% 3 2 66.7%
1 0 0% 1 0 0%
1 1 100% 1 1 100%
1 1 100% 1 1 100%
3 1 33.3% 3 1 33.3%
2 0 0% 2 0 0%
17 12 70.6% 5 2 40.0% 3 3 100% 25 17 68.0%
12 4 33.3% 12 4 33.3%
1 0 0% 4 0 0% 5 0 0%
1 0 0% 39 0 0% 40 0 0%
3 3 100% 29 20 69.0% 61 19 31.1% 8 5 62.5% 6 5 83.3% 5 5 100% 7 2 28.6% 4 2 50.0% 2 1 50.0% 2 2 100% 1 0 0% 1 1 100% 129 65 50.0%
4 4 100% 46 32 69.6% 98 43 43.9% 115 79 68.7% 88 59 67.0% 44 33 75.0% 73 32 43.8% 48 24 50.0% 62 34 54.8% 32 20 62.5% 39 25 64.1% 52 22 42.3% 145 42 29.0% 10 3 30.0% 4 2 50.0% 0 0 0% 1 1 100% 1 0 0% 2 1 50.0% 6 1 16.7% 12 4 33.3% 51 3 5.88% 933 464 49.7%
Updated 30 October 2024
Source: World Health Organization Global Influenza Program Cumulative Cases Report · edit this table


Preparations for a potential epidemic

Main article: Influenza pandemic

"[T]he 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." [24]

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". [25]

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. [26]

See also

References

  1. ^ 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.
  2. ^ 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.
  3. ^ PDF format: H5N1 avian influenza: timeline from the World Health Organization (dated 28 October 2005).
  4. ^ Mortalities from a Flu Pandemic Hard to Predict by Jon Hamilton of National Public Radio Morning Edition, December 16, 2005.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ Bird flu vaccine won't precede pandemic by Jennifer Schultz for United Press International (November 28 2005).
  10. ^ "Avian Influenza: 'Pandemic Vaccine' Appears to Protect Only at High Doses" by Martin Enserink in Science, volume 309, page 996, 12 August 2005 doi:10.1126/science.309.5737.996b
  11. ^ 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.
  12. ^ 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 (29 September 2005) Volume 353 pages 1374-1385.
  13. ^ 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.
  14. ^ 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.
  15. ^ Influenza virus replication in Medical Microbiology, 4th edition edited by Samuel Baron. 1996 Chapter 58. ISBN 0963117211.
  16. ^ Bird Flu Drug Rendered Useless: Chinese Chickens Given Medication Made for Humans By Alan Sipress in the Washington Post Saturday, June 18 2005.
  17. ^ {Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005 October 6;437(7060):889-893}
  18. ^ {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. 2005 October 7;310(5745):77-80}
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