Genetic Changes in Influenza A Virus

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Human influenza virus was first isolated in 1933 Since that time human influenza viruses have been recovered from all parts of the world, and their antigenic properties have been studied in considerable detail, thus providing an opportunity for observing continuing evolutionary changes.

Influenza A virus occurs in humans, swine, horses, birds, and aquatic mammals. Subtypes are classified according to the two envelope antigens, the hemagglutinin (HA, or H) and neuraminidase (NA, or N) All of the fourteen subtypes of the HA molecule have been found in influenza viruses from birds, three of them also in humans, two in pigs, horses, seals, and whales, and one in mink. The nine NA subtypes show a similar distribution.

The outstanding feature ol influenza A virus is the antigenic variability of the envelope glycoproteins, HA and NA, which undergo two types of changes, known as antigenic drift and antigenic shift Antigenic drift occurs within a subtype and involves a gradual accumulation of point mutations; those affecting neutralizing epitopes produce strains each antigenically slightly different from its predecessor. In contrast, antigenic shift involves the sudden acquisition of a gene for a completely new HA or NA, giving rise to a novel subtype that spreads rapidly around the world as most or all humans have no immunity to it.

Antigenic Shift

During the past century there have been five pandemics of human influenza, namely in 1890, 1900, 1918, 1957, and 1968 The pandemic at the end of the First World War killed over 20 million people—more than the war itself. In 1957 the H1NI subtype was suddenly replaced by a new subtype, H2N2, known as "Asian flu" because it originated in China. Within a year over 1 billion people had been infected, but fortunately the mortality was much lower than in 1918, probably because the strain was intrinsically less virulent, although the availability of antibiotics to treat bacterial superinfection undoubtedly saved many lives. In 1968 this subtype was in turn replaced by the "Hong Kong flu" (H3N2). Finally, in 1977 the H1N1 subtype mysteriously reappeared, and since then the two subtypes H3N2 and H1N1 have cocircu-lated

The first clear evidence that distinct mechanisms are involved in the processes of antigenic shift and drift came from peptide mapping and partial amino acid sequencing of HA proteins, which demonstrated relatively close relationships between strains within each of the three human subtypes (HI, up until 1957; H2, 1957-1968; H3, 1968 to the present) but major differences between subtypes, indicating that a sharp discontinuity in the evolutionary pattern had occurred with the emergence of H2 in 1957 and H3 in 1968. With the advent of nucleic acid sequencing it became feasible to determine the complete nucleotide sequence of all eight genes of many strains of influenza viruses isolated from several species of animals and birds. Phylogenetic analysis of the data now indicates that all of the influenza viruses of mammals, including humans, originated from the avian influenza gene pool, which itself presumably evolved from a common ancestral avian influenza virus. In 1957, three of the eight genes (HA, NA, and FBI) of the prevalent human H1N1 subtype were replaced by Eurasian avian influenza genes to produce the human 112N2 subtype; then, in 1968 the human H2N2 subtype acquired new HA and PB1 genes from another avian influenza virus of the Eurasian lineage to produce the human H3N2 subtype. Moreover, retrospective serological studies indicate that the 1890 human pandemic subtype was H2N8, the 1900 subtype H3N8, and the 1918 subtype H1N1, suggesting a pattern of recycling of the three human HA subtypes (HI, H2, H3).

influenza A viruses from birds grow very poorly in humans, and vice versa; indeed, reassortants containing avian internal genes have been tested as experimental vaccines because of their avirulence and their inability to spread from human to human. However, both avian and human influenza virus can replicate in pigs, and genetic reassortment between them can be demonstrated experimentally in that host. An attractive current hypothesis is that antigenic shift in nature occurs when the prevailing human strain of influenza A virus and an avian influenza virus concurrently infect a pig, which serves as a "mixing vessel"; only a reassortant containing mainly genes derived from the human virus but the HA gene derived from the avian virus is able to infect a human and possibly to initiate a pandemic. While such a combination of circumstances may not occur often, it must be appreciated that in rural Southeast Asia, the most densely populated area of the world, hundreds of millions of people live and work in close contact with domesticated pigs and ducks. It is no coincidence that the last two antigenic shifts to produce major pandemics (HI to H2 in 1957, and H2 to H3 in 1968) emanated from China.

Not all episodes of antigenic shift are attributable to genetic reassortment with avion influenza virus The strain of I HNJ (hat reappeared m 1977closely resembled a human H1N1 strain prevalent around 1950. People old enough to have had prior experience of the HJ subtype before it was replaced by 1 i2N2 in 1957 generally still displayed a considerable degree of immunity to it when it reappeared. How H1N1 survived during this long interval is a complete mystery. It is not inconceivable that it may have escaped from a laboratory in which it had been stored frozen since around 1950. Nor is it clear why the HI subtype was supplanted by H2 in 1957 (and 112 by H3 in 1968) yet HI N1 and H3N2 have continued to cocirculate since 1977. Genetic reassortanls between the human H1N1 and H3N2 subtypes have occasionally been isolated from humans since then.

Antigenic Drift

After antigenic shift introduces a new pandemic subtype of influenza A virus, antigenic drift begins. Point mutations occur at random in all segments of the viral genome, a proportion of which result in nonlethal amino acid changes in the corresponding proteins Many of these changes will be deleterious or neutral, but substitutions in antigenic sites on the HA molecule will offer a survival advantage in the presence of neutralizing antibody. Thus amino acid substitutions accumulate in the HA molecule of naturally occurring isolates at the rate of about 1% per annum.

Following the derivation of the three-dimensional structure of the influenza HA molecule by X-ray crystallography (Fig. 4-3) it became possible to map the precise location of all the amino acid changes. Most of the changes in field strains arising in nature by antigenic drift are situated on prominent regions of the exposed surface of the HA molecule in the general vicinity of the receptor-binding pocket.

When monoclonal antibodies are used experimentally to select cscape mutants, each mutant is generally found to contain onlya single amino acid substitution, usually involving a change in charge or side-chain length, or sometimes creating an additional glycosylation site. Clearly, this single substitution is sufficient to prevent that particular monoclonal antibody from binding to its epitope and neutralizing the virion by sterically hindering attachment to the host cell, or by other more poorly understood mechanisms However, fhere are dozens of overlapping epitopes which tend to cluster into five major antigenic sites (Fig. 4-3), and most infected humans produce neutralizing antibodies directed at several or all of these sites Hence, if a variant arising under natural circumstances in an immune or partially immune human is to escape neutralization by the spectrum of anti-HA antibodies present in that individual, it would presumably need to contain mutations in more than one antigenic site. Such multiple mutations would arise only very rarely in a given individual but could accumulate sequentially in successive individuals. All known natural strains arising within the H3 subtype by antigenic drift between 1968 and 1988 (as defined by lack of neutralization by convalescent ferret antisera against previous strains) contained at least four different amino acid changes, located in at least two of the five antigenic sites, always including the immunodominant sites A and B.

Attempts have been made to predict the direction of antigenic drift, in order to prepare appropriate vaccines m advance. Certain amino acid residues

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