They shed the virus and readily transmit it between themselves, but whereas S-OIV has been reported in humans worldwide, it has not yet been reported from a pig farm in the USA October By contrast it has been found in two piggeries each in Australia, Canada and Ireland, and one each in Argentina, Indonesia and Japan. In the outbreaks in Argentina, Australia and Canada, at least, the pigs had not been vaccinated Jorge H. Dillon, J.
Keenliside and Alain Laperle, personal communication , and became infected from infected farm staff. Circumstantial evidence must always be treated with caution. One major uncertainty in trying to determine the origin of S-OIV is that one cannot predict which characters of the parental viruses have remained or changed during the reassortment process that produced S-OIV. If, for example, the significant infectiousness of S-OIV is an 'emergent' property of S-OIV, and not shown by its parents, then one could conclude that the final reassortment probably occurred at about the time it emerged in early However it is not yet known whether S-OIV's infectiousness is novel; the reassortment may have occurred a decade ago, and a recent mutation may have enhanced its infectiousness.
Another widely reported feature of S-OIV is that it replicates poorly in embryonated eggs, but again this may be merely a specific feature of S-OIV and not its immediate parents. Similarly the fact that the evolutionary rate of all of the genes of S-OIV seem to be 'normal' during their unsampled pre-emergent period [ 8 , 11 ]] does not prove that the virus or its parents have been maintained in "unsampled" pig herds and precluded the possibility of human involvement, as viruses grown for vaccines evolve, and indeed might be expected to show an increased evolutionary rate [ 32 , 33 ] while adapting to eggs, a new host, although such an increase may have been offset by the practice of storing 'seed stocks' for use in several 'production cycles' in vaccine production, so that the evolutionary age of a vaccine virus may be less than its sidereal age, and the average could then appear to be 'normal'.
Finally there is the report that the first human S-OIV infections were in Perote, a small Mexican town with a very large number of large piggeries, although it was also reported that none of the pigs showed signs of influenza.
Among the earliest cases were some in Oaxaca, kms to the south [ 34 ]. Perote is an unlikely place for an infected migratory pig to arrive from an intercontinental trip, as the town is in a remote high valley surrounded by mountains, kms to the east of Mexico City where there is the nearest major airport, and kms from the nearest port at Vera Cruz.
The four month difference between 'The Most Recent Common Ancestor' date for S-OIV estimated from its phylogeny [ 8 , 11 ], and its earliest detection in the human population makes it more difficult to make specific conclusions about its provenance. We have also checked whether any extra information about the origin of S-OIV can be gleaned from gene sequence features reported to be associated with host adaptation, virulence, etc. Such sequence signatures must be interpreted with caution as although Genbank records the source host of influenza isolates, it rarely records their passage hosts and passage history.
Influenza viruses are nowadays mostly isolated in MDCK cells, but early influenza isolates were mostly grown in embryonated hen's eggs, and adaptation to eggs is known to cause protein sequence changes [ 32 , 33 , 35 , 36 ].
Therefore we compared sequence signatures and motifs in S-OIV with those of their closest relatives. Subbarao and his colleagues [ 37 ] were first to show that amino acid of the PB2 protein was almost always glutamate in bird isolates and lysine in human isolates.
Chen and colleagues [ 38 ] made a much more extensive survey of sequences and found 51 more sites in 10 of the 11 proteins of influenza virus that discriminated between bird and human isolates as well as, or better than, PB Unfortunately they did not report similarly specific sites for swine isolates, but we have checked whether any of those 52 sites Table 1 in [ 38 ] also distinguish S-OIV and its closest relatives, and found that only two of the 52 sites, PA and NP, did.
At 29 of the sites, the amino acids of the 'S-OIV cluster' i. S-OIV and the swine viruses closest to it are avian-like, at 16 they are human-like, at 6 in the matrix proteins they are novel, and the single recognised site in some NS1s has been lost by truncation. However, surprisingly, all the five recognised sites in the PB1-F2 protein of the S-OIV cluster have human-like residues, whereas the other 11 human-like residues are spread over 40 sites in eight proteins.
In most influenza viruses the PB1 gene encodes three proteins [ 39 , 40 ]. In a small number of influenzas, including all S-OIVs, the PB1-F2 ORF is truncated by termination codons at positions 12, 58 and 88, and its absence is associated with avirulence in mice [ 41 — 43 ]. Trifonov and colleagues have reported statistical tests of various features of the PB1-F2 region [ 26 ], and concluded "that PB1-F2 is of little or no evolutionary significance for the virus".
It seems that the peculiarities of the S-OIV PB1-F2 gene, the human-like signature sites and its selectively super-imposed termination codons, probably reflect the outcome of selection rather than being of "little or no evolutionary significance". Finally, we examined the NS1 protein, which in c. Thus our examination of sequence signatures and motifs in the S-OIV genome has not clarified our knowledge of its origins, but has certainly raised many new questions.
Public confidence in influenza research, and the agribusinesses that are based on influenza's many hosts, has been eroded by several recent events. Measures that might restore confidence include establishing both a unified international administrative framework coordinating all surveillance, research and commercial work with this virus, and also a detailed registry of all influenza isolates held for research and vaccine production.
The phylogenetic information presently available does not identify the source of S-OIV, however it provides some clues, which can be translated into hypotheses of where and how it might have originated. Two contrasting possibilities have been described and discussed in this commentary, but more data are needed to distinguish between them.
It would be especially valuable to have gene sequences of isolates filling the time and phylogenetic gap between those of S-OIV and those closest to it. We believe that these important sequences are most likely to be found in isolates from as-yet-unsampled pig populations or as-yet-unsampled laboratories, especially those holding isolates of all three clusters of viruses closest to those of S-OIV, and involved in vaccine research and production.
Quarantine and trade records of live pigs entering North America could probably focus the search for the unsampled pig population. It is likely that further information about S-OIV's immediate ancestry will be obtained when the unusual features of its PB1-F2 gene are understood.
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Reviews in Medical Virology , 3: Journal of Virology , Three unrelated clusters during March 21—30 suggest that transmission of H1N1pdm09 had begun earlier in southern California.
Convalescent serum samples were collected on April 18, , for patient A and April 17 and May 5, , for patient B. Symptoms were defined as any of the following: cough or sore throat. The presence of subjective fever was not required but was present in some symptomatic patients. Patients were considered to have subclinical infections if they did not report cough, sore throat, or subjective fever.
Information on use of antiviral agents was not systematically collected. Individuals with paired serum samples that demonstrated greater than or equal to fourfold rise in titer by either assay were considered to have seroconverted.
In addition, because specimen collection was not optimal for all participants e. The Centers for Disease Control and Prevention determined that this investigation represented public health response not requiring institutional review board authorization.
Random staggering of paired data points MN and HI titers was used to optimize data presentation. Three close contacts with serologic evidence of H1N1pdm09 infection reported symptoms prior to the onset of symptoms of patient A March 30 and B March 28 Figure 2.
One extended family contact of patient B had a reported onset of illness of March 21, and one household contact of patient B reported onset on March 25; all had extensive contact before and after illness dates.
None of these persons reported travel to Mexico during the week prior to illness onset. The number of patients infected with H1N1pdm09 in the serologic survey or patients infected with H1N1pdm09 or influenza A virus from community surveillance from San Diego and Imperial counties, California, by date of onset of illness from March 21, —April 30, The clusters are not numbered in any specific order.
We provide serological evidence of early community transmission of H1N1pdm09 in southern California in March Also, the H1N1pdm09 outbreak in the United States began slightly earlier than previously documented. The detection of three unrelated clusters of H1N1pdm09 illness in southern California during March 21—30 suggests that community transmission of H1N1pdm09 had begun prior to this time.
The lack of detection of H1N1pdm09 viruses in routine surveillance 8 or reports of respiratory outbreaks Michele Ginsberg and Paula Kriner, personal communication implies that transmission was of limited scope or occurred in populations not easily captured by surveillance, such as persons that do not access standard healthcare providers.
While our sample size was small, this very early serologic investigation during the U. S H1N1 pdm09 pandemic provided some important information that has been corroborated by other studies.
Household contacts had higher SAR compared to other contact types. Also, the household SAR that we report was higher than other reports that used syndromic case definitions or PCR to detect H1N1pdm09 infection, and not serology. We did not limit the contacts in this investigation to household members but included several large extended families, school classmates, and persons with possible occupational exposure.
Thus, transmission in our cohort from early in the pandemic prior to widespread community transmission appeared similar to community transmission at the peak of virus circulation. We used a lower HI cutoff value for seropositivity than other studies e.
Thus, our results are comparable to other reports; the improved sensitivity of both HI and MN added few H1N1pdm09 infections. Our conclusions are limited because of the suboptimal timing of blood draws for all participants and small sample size.
Also, some close contacts reported illnesses several weeks prior to interviews and were not tested for influenza virus infection at the time of illness. Thus, despite serologic evidence for H1N1pdm09 infection, we cannot be certain that the illnesses they recalled were because of H1N1pdm09 infection. Contrasts in codon usage of latent versus productive genes of Epstein-Barr virus: data and hypotheses.
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