Highlight the significance of genetic evolution of H5N1 avian flu
LU Jia-hai, ZHANG Ding-mei, WANG Guo-ling
Summary from Sun Yat-sen University, Guangzhou ,China
A growing concern has focused on the recent identification of influenza A H5N1 virus in Asia. Previously thought to infect only wild birds and poultry, H5N1 has now infected humans, cats, pigs, and other mammals in an ongoing outbreak, often with fatal results.
According to a report from the World Health Organization (WHO), 217 human H5N1 cases have been confirmed and 123 of them have been fatal as of May 19, 2006.1 But many questions remain unanswered, for example how the H5N1 virus could cross species barriers and acquire the ability to infect humans; when and how the H5N1 virus will transmit effectively between humans and cause an influenza pandemic; and what are the determinants of its high virulence.
This article summarizes research progress on the origin of H5N1 virus, factors determining pathogenicity, the contribution of genetic evolution to H5N1 species barrier traversal, human-to-human transmission, and problems in prevention and treatment of H5N1 avian influenza virus.
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It is not known when, or even if, the H5N1 virus will evolve effective human-to-human transmission. The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only ten amino acids from the avian influenza virus consensus sequence (PB2 199Ala¡úSer, PB2 475Leu¡úMet, PB2 567Asp¡úAsn, PB2 627Glu¡úLys, PB1 375Asn/Thr¡úSer, PA 55Asp¡úAsn, PA 100Val¡úAla, PA 382Glu¡úAsp, PA 552Thr¡úSer). Many or all of these residues must account for the ability of the polymerase complex to acquire human transmissibility by an avian influenza virus. The seven human forms out of the ten polymerase residues have already been observed individually in currently circulating H5N1 influenza viruses isolated from birds and humans. Under the selective pressure of a suboptimal growth rate in humans, the polymerase genes of an avian H5N1 virus that is currently circulating could potentially mutate at these ten residues and convert to the ¡°human¡± forms. As a result, the virus may become better suited for efficient human-to-human transmission.3,4,17 Even if human-to-human transmission has not been conclusively identified at this point, we can anticipate that with more human cases, the risk of a more efficient human-to-human transmission of the virus remains a possibility.38
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CONCLUSION
Avian species constitute the origin of the human H5N1 avian influenza virus. The virus has not yet manifested effective human-to-human transmission, but the situation may change if the virus continues to mutate and assort during an epidemic.
To respond to the H5N1 outbreak, it is necessary to detect the variation trends in the virus. To develop effective vaccine and drugs, it is important to clarify variation trends, the molecular epidemic character, and the pathogenic basis and the molecular mechanism allowing the virus to cross the species barrier.
In Netherlands/Germany in 2003, the highly pathogenic H7N7 influenza viruses that was lethal to poultry infected the eyes of more than 80 people and killed one person;
H6 and H9 have spread from a wild aquatic bird reservoir to domestic poultry over the past 10 years.
H9N2 viruses have also been associated with human infections in the mainland of China and Hong Kong.
Avian influenza H10N7 seems to have crossed the species barrier from poultry to people for the first time.
Hence, it is possible that the next influenza pandemic may not be due to H5N1
http://www.cmj.org/Periodical/paperlist.asp?id=LW200694391205609707&linkintype=pubmed
The situation may be more similar to TB, where many of us are "positive" from an exposure, but never had it.
It may depend on your definition of an "infection" - is it anything that elicits a response from your immune system, or is it when a disease temporarily overcomes your immune system?
But when analyzing infectivity, those thousands of "silent" H7N7 responses clearly accurately portray the RBS mutations.
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How do they compare, re: fatalities?
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Fatalities in mice with WSN/33 and the 1918 pandemic H and N on a WSN/33 genetic background are comparable (but both WSN/33 and the 1918 strain are human, and therefore have the 10 changes).
However, none of the recent pandemics (1918, 1957, 1968) involved a polybasic HA cleavage site, which appears to be able to circumvent other changes. H5N1 can grow to high levels in human upper and lower respiratory tract, and can cause fatalities at a rate markedly higher than 1918.
The high levels in the upper respiratory tract strongly suggests that an H5N1 pandemic is one sneeze away.
There is also NO data indicating that ANY of the 10 differences happened in 1918.
The H1N1 1918 pandemic vurus was a recombinant between human and swine H1N1, and both human and swine H1N1 have all 10 changes.
Apart from the people who had actual symptoms, they proceeded to test for antibodies in family members and other contacts, and found so many (more than 1000 if I remember correctly) that they simply stopped testing. Nobody was sick, so what's the point. Money and shifting priorities I guess.
In fact there may be thousands of people with H7 antibodies in the Netherlands.
What does this predict for human influenza?
Might we be facing an increasing number of serious influenzas, since AI seems to be perfecting the art of creating HPAI for mammals in a similar way as domestic fowl?
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Polybasic HA cleavage sites have only been found in H5 and H7 (human is H1 and H3)
Mammalian H5N1 Evolution in Indonesia
Recombinomics Commentary
October 7, 2006
The recent announcements of H5N1 bird flu in cats in Indonesia (http://www.recombinomics.com/News/10070601/H5N1_Indonesia_Cats.html), coupled with results from expanded sequencing of poultry (http://www.recombinomics.com/News/10050602/H5N1_Indo_Match_Failures.html) strongly signal the existence of a separate mammalian H5N1 reservoir in Indonesia that is responsible for the vast majority of human cases.
This separate reservoir creates significant problems, because most of the attention has focused on infected poultry, and the mammalian reservoir has been significantly under investigated and under reported.
Therefore, a review of the evolution of this mammalian reservoir is useful. Although Indonesia did not acknowledge H5N1 infections until 2004, the first isolates were from birds in 2003. Sequence analysis of the 2003 and 2004 isolates indicated the H5N1 was Clade 2 and had a number of genetic markers that were specific for Indonesia.
The first human case was reported in July of 2005, and the sequence of the isolate, A/Indonesia/5 (http://flu.lanl.gov/search/view_record.html?accession=ISDN125873&database=fluA)/2005 had the Indonesia specific markers, but also had a number of unique polymorphisms, including one that created a novel HA cleavage site (http://www.recombinomics.com/News/03260601/H5N1_Vaccine_Indo_Sequence.html), RESRRKKR. However, the second human isolate, A/Indonesia/6/2005 had the more common HA cleavage site, RERRRKKR, and was similar to bird isolates. Subsequent human isolates in 2005 had the novel cleavage site, but several had an additional silent change, so although the cleavage site matched the first sequence at the protein level, there were a number of changes at the nucleotide level that divided the sequences with the novel cleavage site into two groups.
However, as the number of sequences increased in early 2006, it became increasingly clear that the human sequences were separating from the poultry sequences, all of which had the common bird cleavage site. The first match of the human sequences was from H5N1 from a throat swab of a cat (http://effectmeasure.blogspot.com/2006/02/indonesia-and-questions-about-its.html) in Indramayu near a residence were two siblings died from H5N1 infections. The sequence of the cat isolate not only matched the more recent human sequences, but was very close to the sequences of the isolates from the two siblings, A/Indonesia/283H/2006 and A/Indonesia/286H/2006, as well as other human isolates from Indramayu, A/Indonesia/292H/2006 and A/Indonesia/304H/2006. New isolates in 2006 collected from patients in East and West Java were sequenced and all were matches of more recent sequences such as the four human and one cat isolate from Indramayu.
In May of 2006 however, there was a new cluster in the Karo regency in north Sumatra. This outbreak was the largest to date and involve secondary and tertiary transmissions of H5N1. Consequently a meeting was call by WHO and consultants in Jakarta in June. Included in the presentation was a phylogenetic tree (http://www.recombinomics.com/phylo/Indo_Karo_HA1.html) that summarized the H5N1 Indonesian isolates as of June 12, 2006.
The tree, which had the human sequences in green and the Karo cluster shaded in pink, clearly showed the match problem. All of the sequences with the novel cleavage site were on the lower portion of the tree and there were no poultry sequences on these two lower branches. Moreover, all of the recent human sequences from Java were on the lowest branch, which was even further from the poultry isolates. Thus, the human isolates were evolving away from the poultry isolates, suggesting the existence of a separate mammalian reservoir.
However, all of the human isolates were from July, 2005 or later, while most of the bird isolates were from earlier dates. Therefore 91 samples (http://www.recombinomics.com/News/08120601/H5N1_Match_Unlikely.html) were schedule for shipment to Australia for virus isolation and sequencing. The samples were from infections between September, 2005 and March, 2006.
As sequences from these more recent and geographically dispersed isolates began to be published, it was becoming increasingly clear that the vast majority of the human infections on Java were not from domestic poultry (http://www.recombinomics.com/News/08120601/H5N1_Match_Unlikely.html). Each human sequence mapped to the lower portion of the tree and which was more distinct from the bird sequences.
The second set of new bird sequences included an isolate with the novel cleavage site. It was from a duck on Indramayu (http://www.recombinomics.com/News/08310601/H5N1_Indo_Duck_Cleavage.html) isolated in 2006. However, that isolate match the upper branch of the human sequences, which were composed of six isolates from three patients in 2005. Thus, although every human isolate in 2006 was matching the lower branch, the one duck sequence matched the upper branch.
The third set of poultry sequence had two matched with the lower branch. However, the two matches were from chickens in central Sumatra from 2005. Thus, none of the poultry isolates matched the lower human branch, while all human isolates, as well as the cat isolate, matched the lower human branch.
These data again supported a separate reservoir for the human sequences, and the only matches on Java were from the one cat, and all human isolates. The recent announcement indicates more H5N1 has been detected in cats, but the sequences of those isolates have not been released. Swine H5N1 sequences have been reported, but none match (http://www.recombinomics.com/phylo/Nidom_swine_HA.html) the human sequences.
The match failures pose a major problem because testing of humans is largely limited to patients how have been near dead or dying poultry. However, the poultry association has not been linked to the human infections, so an expanded testing of patients with symptoms is warranted. Similarly, more sequencing of H5N1 from other reservoirs is warranted by the match failures between mammalian and avian sequences.
H6 and H9 have spread from a wild aquatic bird reservoir to domestic poultry over the past 10 years.
H9N2 viruses have also been associated with human infections in the mainland of China and Hong Kong.
Avian influenza H10N7 seems to have crossed the species barrier from poultry to people for the first time.
Hence, it is possible that the next influenza pandemic may not be due to H5N1
Yes but H5N1 is the most massively spread and out of control. All others subtype examples are singles emergent cases the same way H5N1 was back in 1997 but water flowed under the bridge since that time.
While the virus was isolated from 80-some people is fine and dandy.
estimates based on the number of workers and their family members testing seropositive for H7N7 indicate 1 to 2 thousand people are/were seropositive for H7N7. Would anyone consider a person who is sero positive for HIV to not have it? No, of course not.. so How can they NOT include all the people that are sero positive for nfluenza H7N7 in the total number? or Why didn't they?
WHO hopes H7N7 also reads their press releases.
However, none of the recent pandemics (1918, 1957, 1968) involved a polybasic HA cleavage site, which appears to be able to circumvent other changes. ..........
in http://www.flutrackers.com/forum/newreply.php?do=newreply&p=28979
The difference between LPAI and HPAI is the HA clevage site. HPAI has multiple basic amino acids (R or K) at the cleavge site, like RERRRKKR for the most common H5N1 in Asia, or GERRRKKR for the Qinghai strain, or RERRRKR for the Fujian strain.
LPAI has only 1 R at the cleavage site.
The other HPAI have a 3-4 basic amino acids at the HA cleavage site
What does this predict for human influenza?
Might we be facing an increasing number of serious influenzas, since AI seems to be perfecting the art of creating HPAI for mammals in a similar way as domestic fowl?
.
While the virus was isolated from 80-some people is fine and dandy.
estimates based on the number of workers and their family members testing seropositive for H7N7 indicate 1 to 2 thousand people are/were seropositive for H7N7. Would anyone consider a person who is sero positive for HIV to not have it? No, of course not.. so How can they NOT include all the people that are sero positive for nfluenza H7N7 in the total number? or Why didn't they?
In Netherlands/Germany in 2003, the highly pathogenic H7N7 influenza viruses that was lethal to poultry infected the eyes of more than 80 people and killed one person;
How does the current polybasic HA cleavage site's contribution to fatalities compare to 1918 NA deletion that bound plasminogen and allowed it to cleave anywhere there was blood flowing?
How do they compare, re: fatalities?
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