Whole-Genome Analysis of Human Influenza A Virus R

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Isolates from different geographical locations are color coded according to the inset map.

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Note that there is remarkable genetic diversity, manifest as the circulation of multiple lineages likely to be independently imported, and that there is no clear spatial patterning, as reflected in the mix of colors. Figure adapted with permission from PLoS Pathogens The genomic revolution was also central to the realization that a global source population for human influenza A virus — most likely centered in East and Southeast Asia — annually provides the antigenic variants that ignite the seasonal influenza epidemics in the sink populations of the Northern and Southern Hemispheres 16 , Southeast Asia fits the bill for a global influenza source because its large, dense, and well-connected populations provide exactly the conditions that allow natural selection manifest as ongoing antigenic evolution in the HA and NA proteins to operate with maximum efficiency Figure 3.

Not only is this observation important from the perspective of basic epidemiology — this is the geographic region that needs to be surveyed most intensively for emergent viruses — but it may also have a major bearing on vaccine design. Vaccines designed to prevent infection with human influenza A viruses tend to fail every few years because of a periodic burst of antigenic evolution, in which a virus emerges with more mutations in the HA protein than predicted Knowing where these antigenic strains are generated every year should speed up the process of choosing the influenza A strain to be incorporated into the vaccine and also yield more effective choices.

Global migration of influenza A virus.

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The virus is thought to be exported directly from the circulation network in East and Southeast Asia to Australia, Europe, and North America. Figure adapted with permission from Science The expanse of genomic information about influenza A viruses has also shed new light on the evolution of drug resistance. The most interesting observation from this perspective is that, remarkably, direct drug-selection pressure may not always be responsible for the rise of drug resistance. Resistance in this case is caused by a single amino acid change — Ser31Asn — in the viral M2 protein, an ion channel that is the target of adamantanes.

To the surprise of many, the frequency of the Ser31Asn mutation has risen abruptly in populations where adamantanes are rarely used, such as the United States. The most likely explanation for the global dissemination of Ser31Asn is therefore that it became fortuitously linked to another beneficial mutation — probably conferring immune escape — located elsewhere in the viral genome This again tells us that genome-wide interactions are a critical aspect of viral genetics.

Rate of PCV2 recombination not widely recognised

Incredibly, exactly the same process of genetic hitchhiking now seems to be taking place with resistance to oseltamivir, a major NA inhibitor. Because these drugs are not widely used in European populations, linkage to another beneficial mutation seems the most probable explanation for the rise of viruses carrying HisTyr, although this needs to be formally assessed.

What the IGSP has not provided is clear information on whether there is a viral genetic basis to the variance in clinical presentation of influenza in humans i. This kind of analysis is clearly a major goal of second-generation studies in RNA virus genomics. In my opinion, there are a number of reasons, all of which are surmountable, why genomic data from influenza A virus have thus far been of limited use for clinical studies.

First, the available sample of sequences, although huge from a genomics perspective, is still small relative to those normally used in clinical epidemiology. Thankfully, advances in sequencing technology mean that this major barrier will soon be breached 1. Second, the isolates of influenza A virus chosen for sequencing evidently do not amass a representative sample of those that circulate in human populations, as they were taken from patients who were ill enough to seek medical attention.

Hence, there is necessarily a profound sampling bias against low virulence — even asymptomatic — strains of influenza A virus. Last, it is clear that most mortality among patients with influenza disease is due to secondary bacterial pneumonia caused by Streptococcus pneumoniae ; ref. Hence, it is impossible to discuss the epidemiology of influenza virus out of context of the other pathogens that cocirculate during the influenza season Modern genomic data now tells us that this antigenically distinct variant of HA was acquired by reassortment from an as-yet unidentified source , further emphasizing how processes of genetic exchange can alter viral phenotype Finally, despite the genomic revolution, there are still aspects of the evolution and epidemiology of influenza A virus that remain uncertain but may be central to its future control.

Second, and of more clinical importance, it is essential that we understand the rules by which antigenic evolution occurs in influenza A virus 31 , Specifically, if it were possible to determine how and why large antigenic changes occur periodically — how the virus moves from antigenic type to antigenic type — it would doubtless be possible to design vaccines that are far more effective vaccines, perhaps even evolution proof.

It is therefore essential that future genome sequence data be gathered with an associated measure of viral antigenicity, such as hemagglutinin-inhibition distance, which depicts the differing ability of isolates of influenza virus to agglutinate red blood cells and the corresponding ability of antisera raised against these isolates to inhibit agglutination There has been depressingly little progress toward an HIV vaccine, reflecting a marked lack of protective immunity in both human and animal trials.

Although there is more genomic sequence data for HIV than for any other virus, and this has told us a great deal about its biology, genomics has yet to contribute much to HIV vaccine development. Given the current impasse in vaccine development, debates over how phylogenetics should assist in deciding which HIV strain to use are perhaps overly optimistic 34 , In stark contrast, the study of the origins, evolution, and molecular epidemiology of HIV has been wildly successful: we now know approximately when both types of AIDS virus HIV-1 and HIV-2 first appeared in humans; we now know roughly where these emergence events took place; and we can make more than an educated guess about the precise mechanisms of cross-species transmission 36 — Hence, for HIV-1, the most prevalent and clinically relevant type of HIV, analysis of genomic sequence data has told us that this virus most likely jumped from common chimpanzees Pan troglodytes troglodytes to humans on multiple occasions during the early years of the twentieth century, and that this occurred somewhere in West and Central Africa, probably through the preparation and consumption of virally infected bushmeat.

These early epidemic embers were fanned by an expanding logging industry as well as the urbanization of West and Central Africa 39 — Recent dating studies using molecular clocks, in which it is assumed that viral mutations accumulate through time at a fairly constant rate so that divergence times can be estimated across phylogenetic trees 42 , have also suggested that HIV-1 first entered the Western Hemisphere during the s, although it was not detected as a clinical disease AIDS until some years later The other major insight stemming from genomic approaches to studying HIV-1 is that this virus is highly genetically diverse, both within an individual host and on a global scale Currently, there are 9 recognized genetic subtypes of HIV-1 A—K, excluding E and I as well as 35 circulating recombinant forms CRFs , which are created by frequent intersubtype recombination i.

Some of these CRFs are complex, which indicates that individual hosts were infected by multiple viruses — again highlighting the lack of cross-protective immunity — followed by frequent recombination. Indeed, intersubtype recombination is so common in HIV-1, it is arguable that the subtypes — originally described as discrete phylogenetic entities — do not exist at all.

Rather, what are thought of as HIV-1 subtypes are merely clusters of sequences that were generated by a series of localized outbreaks in specific populations The ultimate demise of the subtype concept also confounds attempts to associate particular viral lineages with specific disease manifestations. Indeed, it is notable that few studies have proposed associations between different HIV subtypes and specific phenotypic features 46 , 47 , some of which have not withstood further scrutiny Although it is often stated that the success of HIV-1 is due to its capacity for rapid mutation, this idea lacks some important context.

Estimates of the intrinsic mutation rate for HIV-1, reflecting the process of replication with a highly error-prone reverse transcriptase enzyme, place this in the realm of 0. While this mutation rate is evidently far higher than those observed in organisms with double-strand DNA, it may still be 5-fold lower than that in RNA viruses that replicate using the even more error-prone RNA-dependent RNA polymerase, in which mutation rates frequently reach approximately 1.

As a consequence, while it is certainly the case that the raw material for genetic variation in HIV-1 is produced by mutation, the subsequent processes of recombination and natural selection for immune escape are equally responsible for the complex and abundant genetic diversity in this virus Finding up-to-date, useful information about welfare best practice can be a real headache but AHDB Pork provides a plethora of tools for the forward-thinking pig farmer.

South Korea and the Philippines are two additions to the list of regions with confirmed outbreaks of African swine fever in Asia, which now totals nine. Recombination of porcine circovirus type 2 PCV2 is a known phenomenon in the research arena. What is the rate of PCV2 recombination? What PCV2 strains are found in recombinants? What vaccine strategy then is likely to protect pigs against PCV2 recombinants?

Three major clusters of sequences were apparent in phylogenetic trees of the complete genomes of H3N2 influenza A viruses sampled from New York State. These corresponded to particular influenza seasons winter months : a —, b — and — together although only five members of latter season are present in these data , and c — Figure 1. Such temporal structure is commonly observed in trees of influenza A virus, and this is thought to be largely driven by positive selection acting on the HA gene [ 17 ]. However, a number of isolates did not fall into these three groups. We have denoted the two groups of viruses circulating after the — season as clade A the major cluster after the — season and clade B the minor cluster comprising isolates 32, , and The maximum likelihood phylogenetic tree is mid-point rooted for purposes of clarity, and all horizontal branch lengths are drawn to scale.

Bootstrap values are shown for key nodes. To investigate the evolutionary history of the outlier viruses in more detail we inferred phylogenetic trees for each of the eight individual gene segments Figure 2. Strikingly, although the distinction between clades A, B, and C was apparent in seven of the eight genes, no such separation was seen in the HA phylogeny.

In this case, clades B and C clearly clustered within clade A and with strong bootstrap support. The close phylogenetic relationship of these three groups of viruses in HA set against a background of genetic divergence in all other segments strongly suggests that these data contain evidence for at least two independent reassortment events, one involving clades A and B and another involving clade C and either clade A or clade B.

In the case of the clade C viruses, the separate gene phylogenies also reveal that these isolates share a common ancestry with viruses first sampled during the — season, while the clade B viruses share a closer relationship with those viruses of the — season.

All maximum likelihood phylogenetic trees are mid-point rooted for purposes of clarity only, and all horizontal branch lengths are drawn to scale. Bootstrap values are shown for clades A, B, and C.

Influenza A virus - Wikipedia

Colors are as in Figure 1. Two more major phylogenetic displacements suggestive of reassortment involving other segments were similarly identified. To determine the direction of the reassortment events in HA, we inferred phylogenetic trees of larger datasets comprising the New York State isolates and representatives of the other human and swine H3N2 viruses sampled during the same time period. Because sequences from the core genes have only been sporadically collected, this analysis necessarily focused on HA and NA.

As expected from the phylogenetic analysis of the New York State viruses, the distinction between clades A, B, and C was apparent in the NA gene tree Figure 3 as well as the core genes trees shown in Figure S1. Hence, although clade B was at low frequency in the New York State dataset, it represents a distinct lineage of H3N2 viruses globally circulating from at least to The maximum likelihood phylogenetic tree is mid-point rooted for purposes of clarity only, and all horizontal branch lengths are drawn to scale.

A very different evolutionary history was revealed in HA. In this case, clade A of the New York State viruses expanded to contain the majority of viruses sampled after and from a variety of locations Asia, Australasia, Europe, and North America , as well as a number of Asian viruses from Figure 4. This large group of viruses then clustered within clade B, such that most clade B viruses sampled from to formed a clear, but closely related, outgroup to the later clade A viruses, with the remaining clade B viruses falling within clade A Figure 4.

The three clade C viruses also fell within this expanded clade A.

Such a phylogenetic pattern strongly suggests that the HA from both the clade A and clade C viruses was acquired from that present in clade B through reassortment. Further, the fact that the clade A and B isolates closest to the phylogenetic location of the reassortment event were both sampled in suggests that the reassortment occurred in this year, although pinpointing the exact phylogenetic location of the recombinant event is difficult given the relatively small number of samples available from this critical time period.

Similarly, the fact that these viruses had Asian origins is also compatible with the reassortment event occurring in this region, a hypothesis also supported by a recent analysis of comparable partial genomic analysis of H3N2 isolates from the southern hemisphere [ 28 ]. The maximum likelihood phylogenetic tree is rooted on a divergent set of human and swine viruses for purposes of clarity only, and all horizontal branch lengths are drawn to scale.

Colors are as in Figure 1 , with yellow indicating all those viruses identified as clade B viruses from the analysis of the expanded NA dataset.

Draco antiviral project

The phylogenetic location of the reassortment event between clades A and B was set at the position of the most basal clade A virus, defined on the basis of the NA analysis, within the older clade B. The phylogenetic locations of the two critical antigenic mutations at sites and are also shown. Because both clade A and clade B contain viruses sampled on a near global basis, it is important to determine possible phenotypic differences between them.

Table 1 shows the amino acid replacements that consistently distinguish the clade A and B viruses. These changes are not uniformly distributed among the seven segments not including HA. Our analysis of whole genomes of H3N2 influenza A viruses sampled during — has identified two key evolutionary patterns. First, although the majority of viruses isolated after fall into a single phylogenetic group clade A , multiple, co-circulating viral lineages are present at particular time points.

The genetic diversity of influenza A virus is therefore not as restricted as previously suggested, particularly when genes other than that encoding HA are analyzed.

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This co-circulation of lineages is most apparent with the identification of three clades of H3N2 viruses that appear to infect the same populations until , after which they acquired a common HA gene through reassortment. Second, and more dramatically, these multiple, co-circulating lineages may have complex genealogical histories and interact through reassortment. Indeed, we have documented two reassortment events involving the HA gene of clade B: one in which it was acquired by the clade A viruses and another in which it was independently acquired by those isolates assigned to clade C.

Two further reassortment events involving the PB2 and PA genes were also evident from our phylogenetic analysis. Given that we are only able to reliably detect reassortment when it is associated with major changes in tree topology, it is likely that reassortment among closely related lineages is also commonplace in influenza A viruses.

Reassortment between influenza A viruses has been described in both human and animal viruses [ 1 , 29 ]. Notably, antigenic shift by reassortment between human and avian influenza A viruses has been documented in the formation of the H2N2 and H3N2 pandemics [ 30 — 32 ]. Other recent examples of reassortment between human and animal influenza A viruses have resulted in the emergence of novel H3N2 and H1N2 swine viruses in North America and Europe [ 33 , 34 ] and the evolution of H5N1 viruses in Asia from to the present [ 35 ].

Reassortment between co-circulating lineages of human influenza A and more recently influenza B viruses following mixed infection has also been described [ 36 — 41 ]. For example, human H2N2 viruses formed two distinct clades in the s prior to the emergence of the H3N2 pandemic virus, with one virus a reassortant containing genes of both clades [ 42 ].

Reassortment between H3N2 and H2N2 viruses may therefore have assisted successful cross-species transmission [ 42 ]. Reassortant viruses were also described following the re-emergence of the H1N1 subtype in that did not replace the previously circulating H3N2 viruses. In this case, co-circulation of influenza viruses of both subtypes continued, and co-infection with both subtypes was reported [ 43 ].

While reassortant H3N1 strains were not isolated, H1N1 strains containing reassorted internal protein-encoding gene segments from H3N2 viruses were observed [ 44 , 45 ]. Occasional isolates of H1N2 viruses were also detected after the re-emergence of H1N1 [ 46 , 47 ]. More recently, the widespread circulation of viruses with the H1N2 subtype has been documented [ 41 ]. These viruses contained the HA segment of contemporary H1N1 viruses reassorted onto an H3N2 background, a reassortment pattern similar to that observed with the sporadically circulating H1N2 viruses of the s and early s [ 47 ] and to the dominant reassortments described in this analysis.

Since the H1 and N2 subtype proteins were antigenically and genetically similar to co-circulating H1N1 and H3N2 subtype viruses, the emergence of this new subtype did not result in an epidemiologically significant event [ 41 ]. Reassortment among co-circulating clades of H3N2 viruses like that observed in the current study has also been previously described, including reassortment of the NA gene segment [ 48 ] and the core protein-encoding segments [ 49 ]. Most prior phylogenetic studies of human influenza A have suggested that inter-pandemic evolution may be essentially described as a series of successions by variants of the previous season's dominant strain.

These successions are largely determined by strong positive selection acting on the abundance of mutational diversity in the HA of the dominant strain. However, we found that at least four reassortment events occurred among human viruses during the period — and that two of these involved a major change in HA. Recently, Barr et al.

To our knowledge, these analyses are the first demonstrations of the emergence of a major antigenically variant virus derived by reassortment between two distinct clades of co-circulating H3N2 viruses rather than by antigenic drift.

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