Pretty good article, updated 2-20-06, with description of the structure of H5N1, as background for previous post. Excerpt follows.
en.wikipedia.org
"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 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."[14]
* Surface antigen encoding gene segments (RNA molecule): (HA, NA)
o 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."[15] 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. [16]
o 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)[17]
o 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 [18]. The amino acid substitution (Ser31Asn) in M2 some H5N1 genotypes is associated with amantadine resistance[19].
o NP codes for nucleoprotein.
o 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"[20][21]
+ NS1: Non-structural: nucleus; effects on cellular RNA transport, splicing, translation. Anti-interferon protein. NS1 described in 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"[22]. 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."[23]
+ NEP: The "nuclear export protein (NEP, formerly referred to as the NS2 protein) mediates the export of vRNPs" [24]
o PA codes for the PA protein which is a critical component of the viral polymerase.
o 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."[25] This was discovered by Chen et. al. and reported in Nature[26].
o 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.[27][28] 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[29]. 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[30]. 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"[31]. 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 [32] has shown that the 1918 virus, like H5N1, was also an avian influenza virus. Furthermore, Tumpey and colleagues [33] 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."
en.wikipedia.org |
