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Flu mutation: Critical H1N1 Cases In India
The 16 Jul. 2010 at 09:19Last newsComments (0)Add a comment
Recombinomics Commentary 23:53
July 15, 2010
A West Bengal minister is stated to be in a critical condition after being struck by swine flu as six fresh cases of the infection were on Thursday reported taking the total number of those being afflicted to 12 in the city.
West Bengal Water Resources Minister Nandagopal Bhattacharya has been diagnosed with the infection, state health department's nodal officer for swine flu Asit Biswas said here.
Health Minister Suryakanta Mishra said the throat swab of Bhattacharya, already admitted in a city clinic with respiratory distress and brain haemorrhage, has tested positive.
The minister's office in the state secretariat said his condition was critical. "His swab was found positive by the National Institute of Cholera and Enteric Diseases," his office said.
Five of those infected in the city proper and Dum Dum in the northern outskirts have been admitted to various hospitals including the state-run I D hospital at Beliaghata.
In 2009, 135 persons were affected by swineflu, but no one died.
The above comments describe confirmed H1N1 cases in West Bengal, including the Water Resources Minister (25M). These confirmed cases are likely to be a small set of H1N1 infections in West Begal, which represent a small sub-set of cases in India. The clinical picture of the minister raises concerns that the first confirmed H1N1 fatality in West Bengal will be reported soon. These early critical cases have raised concern that the next H1N1 wave may be more virulent.
Sequence analysis of H1N1 in later 2009 or early 2010 identified an increased frequency of sequences with D225G, including several fatal cases in India. A handful of sequences had D225G along with G158E, a change that facilitates escape of immune responses against wild type H1N1.
A recent sequence (collected June 30, 2010) had D225G and G158E in Nanjing, China. Neither marker was present in the vast majority of 2010 sequences collected throughout China in the winter / spring.
A increased frequency of D225G could have catastrophic effects. Two of the five HA sequences from fatal cases in 1918/1919 had D225G, which is frequently found in swine sequences. Pandemic H1N1 is transmitting swine to swine in the United States, as is G158E. Further increases in the frequency of G158E or D225G/N would be cause for concern.
Recombination and G158E Duplication In H1N1 Iowa Swine
The 06 Jul. 2010 at 18:28Last newsComments (0)Add a comment
Recombinomics Commentary 16:50
July 6, 2010
The recently released HA sequence from A/swine/Iowa/03032/2010 has a six BP duplication which includes G158E. Thus instead of the wild type sequence for positions 156-159 changing from KKGN to KKEN, as found in many low reactors, the Iowa swine sequence has KKEKEN, which almost certainly leads to significant immunological escape.
The isolate was collected a month ago and the genetic background is similar to humans infected by swine H1N1 in 2007 in Ohio. However, the sequence has also acquired pH1N1 sequences that are found in almost all pH1N1 isolates. Moreover, most of these polymorphisms are non-synonymous and at least one polymorphism traces back to 1918.
These acquisitions raise concerns that this virus could quickly gain efficient and sustained transmission in humans, leading to a co-circulating H1N1 pandemic.
More intense screening of swine in the United States would be useful.
Widespread pH1N1 Low Reactors In Europe
The 07 May. 2010 at 06:06Last newsComments (0)Add a comment
Recombinomics Commentary 19:37
May 6, 2010
Mill Hill has released a series of HA and NA sequences (at GISAID) from Europe. These sequences are from late 2009, early 2010, and have increased frequencies of changes associated with low reactors (positions 157-159) as well as pseudospecies at position 225 (D225G, D225N, D225E). The most common low reactor changes were pseudospecies at position 158. These low reactor sequences were on multiple backgrounds and cluster on specific branches.The appearance of the same polymorphism on multiple branches signals spread by homologous recombination, while the clustering on specific branches signals spread by clonal expansion. Similar results were seen in a large series in Germany, which followed similar patterns in the United States and Japan.
These increases in low reactors most commonly involve psuedospecies at position 158. Such changes were discussed in the paper describing the selection of a California/7 vaccine target. Isolate with G158E grew well in eggs, reflecting an increased affinity for gal 2,3 receptors. However, G158E was not included because of the marked reduction in titer in antisera directed against wild type California/7. The low reactor linkage to G158E was also seen in escape mutants, which had G158E, as well as testing of German isolates by Mill Hill and CDC. Both labs designated isolates with D158E was "low reactors".
However, subsequent isolates from the US which had G158E were not designated low reactors, suggest a change in antisera by the CDC. This antisera appears to have limited ability to detect low reactors, because all recent US low reactors designated by the CDC have changes at position 159. Positions 157-159 map to the same antigenic sites, and changes at all three positions has been linked to low reactor status or immunological escape.
The failure of the CDC to designate US isolates with G158E as low reactors raises concerns that such important changes are circulating undetected. Since the changes is usually detected as a pseudospecies, the ration of G158E to G158 may vary within the host. Samples from the upper respiratory tract would have higher frequencies of wild type, while lung samples would have higher concentrations of G158E. Thus, the G158E may not be detected in direct sequencing, especially if samples are collected early or from the upper respiratory tract.
The position 158 pseudotypes are similar to position 225 psuedotypes, which also have a component, D225G, which targets the lung. D225G is also increasing dues to recombination and clonal expansion, and the number of sequences with G158E and D225G continue to rise. In the latest series, A/Georgia/4484/2009, collected on Dec 21, 2009 has G158E and D225G.
D225G D225N G158E Pseudospecies in Fatal Japan pH1N1 Case
The 20 Apr. 2010 at 20:58Last newsComments (0)Add a comment
Recombinomics Commentary 17:56
April 20, 2010
/strain="A/Nagano/RC1/2009(H1N1)"
/serotype="H1N1"
/isolation_source="gender:M; age:33; Autopsy lung"
/note="HA-Major (detected at 75%)"The above description is from one of three HA sequences from the same patient. The initial sequence was deposited by NIID Japan at GISAID last year and had D225G. The two more recent sequences were deposited at Genbank. The above deposit had mixed signals at position 158 and 225. At 158, G158E was mixed with wild type. At position 225, mixed signals were at codon positions one and two, coding for D225G and D22GN. In the third sequence, representing a minor (25%) species, there was G158E and D225N.
These data were all from the same patient (33M), who tested negative for H1N1 and was not treated with oseltamivir. pH1N1 was identified in autopsy lung, which has been described in the publication, "The first autopsy case of pandemic influenza (A/H1N1pdm) virus infection in Japan: detection of a high copy number of the virus in type II alveolar epithelial cells by pathological and virological examination". Another paper in PLOS One is in press.
These data raise serious questions about the sequences placed on deposit in public databases. The pseudospecies at positions 158 and 225 are common, and vary by sample location and collection from the same patient. Sequences containing both D225G and D225N from fatal cases have been deposited from Ukraine, Moldova, Mexico, and the United States.
In addition, sequences from fatal cases in the Duke death cluster had various combinations. The index case had D225G with wild type in the first collection, and just D225G in the subsequent collection. Another fatal case had D225N with wild type, while a third case was just wild type. However, all of these cases were infected with the same pH1N1 which had the rare HA polymorphism, Y233H, as well as NA H274Y. There is little doubt that all three fatal infections had wild type, D225G, and D225N and various ratios in various collections.
However, in the WHO paper on D225G, the absence of D225G in some direct sequences was used to confuse the D225G situation. Moreover the CDC stated that they had found D225G in only 7 or 8 patients, when they had published D225G sequence from more than 15 patients, suggesting they were discounting samples with D225G in favor of those with wild type. Neither the CDC nor WHO has acknowledged the presence or transmission of D225G or D225N in the Duke death cluster, or any other clusters.
These denials, and the selective release of sequences from patients infected with HA contain D225G and/or D225N continues to be hazardous to the world's health.
H1N1 PB2 E627K In Three Patients In India
The 16 Mar. 2010 at 07:26Last newsComments (0)Add a comment
Recombinomics Commentary 05:36
March 16, 2010
The swine flu virus isolated from the throat swab samples of three H1N1-infected patients at the National Institute of Virology (NIV) has shown a small genetic mutation in the polymerase 2 (PB2) gene, NIV director A C Mishra told TOI on Monday.
The PB2 mutation has previously been associated with increased efficiency of replication and possible virulence changes in other influenza A viruses.
The above comments indicate E627K has been detected in three patients in India. E627K has been found in all human influenza since 1918, so acquisition of the polymorphisms is not a surprise. Some had speculated that it would be acquired from seasonal flu via reassortment, but there have been no reports of any change in the original constellation of genes in pandemic H1N1, which had only one human flu gene, PB1, which was acquired in 1993. The above description indicates the acquisition was a single nucleotide change and was likely due to recombination. The finding of the same change in three patients indicates E627K is transmitting. Prior reports of one isolate in Shanghai or two isolate in The Netherlands did not lead to additional reported transmissions. However, the simultaneous detection in three patients in India suggests the E627K will become widespread.
Multiple reports in the US are signaling recent upticks in H1N1 cases, and it is likely that the new wave will select multiple changes. Increasing rates of acquisitions have been noted, including D225G/N and G158E in HA as well as H274Y in NA.
These recent acquisitions raise concerns of increases in severe and fatal cases. The acquisition of E627K will likely lead to higher levels of H1N1, which would also create more severe cases. E627K allows for more efficient replication at lower temperatures which is linked to more efficient transmission via the upper respiratory tract, while additional HA changes lead to higher levels of H1N1 in lung. Many of the significant polymorphisms have been associated with mixtures, and a mixture of PB2 with E627 and E627K could lead to increases in transmission as well as increases in lethality.
Sequence data in these three patients and relationships to each other would be useful.