Influenza Has Been Responsible for Some of the Worst Pandemics in History

The influenza virus infects the upper respiratory tract and major central airways in humans, horses, birds, pigs, and even seals. In 1918-19, an influenza pandemic (worldwide epidemic) killed more than 20 million people, a toll surpassing the number of casualties in World War I. Some areas, such as Alaska and the Pacific Islands, lost more than half of their population during that pandemic.

PROPERTIES OF THE INFLUENZA VIRUS

Influenza viral particles, or virions, are roughly spherical or ovoid in shape, with an average diameter of 90-100 nm. The virions are surrounded by an outer envelope—a lipid bilayer acquired from the plasma membrane of the infected host cell during the process of budding. Inserted into the envelope are two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which form radiating projections that are visible in electron micrographs (Figure 17-3). The hemagglutinin projections, in the form of trimers, are responsible for the attachment of the virus to host cells. There are approximately 1000 hemagglutinin projections per influenza virion. The hemagglutinin trimer binds to sialic acid groups on host-cell glycoproteins and glycolipids by way of a conserved amino acid sequence that forms a small groove in the hemagglu-tinin molecule. Neuraminidase, as its name indicates, cleaves N-acetylneuraminic (sialic) acid from nascent viral glycoproteins and host-cell membrane glycoproteins, an activity that presumably facilitates viral budding from the infected host cell. Within the envelope, an inner layer of matrix protein surrounds the nucleocapsid, which consists of eight dif-

FIGURE 17-3

Electron micrograph of influenza virus reveals roughly spherical viral particles enclosed in a lipid bilayer with protruding hemagglutinin and neuraminidase glycoprotein spikes. [Courtesy of G. Murti, Department of Virology, St. Jude Children s Research Hospital, Memphis, Tenn.]

FIGURE 17-3

Electron micrograph of influenza virus reveals roughly spherical viral particles enclosed in a lipid bilayer with protruding hemagglutinin and neuraminidase glycoprotein spikes. [Courtesy of G. Murti, Department of Virology, St. Jude Children s Research Hospital, Memphis, Tenn.]

emergence of a new subtype of influenza whose HA and possibly also NA are considerably different from that of the virus present in a preceding epidemic.

The first time a human influenza virus was isolated was in 1934; this virus was given the subtype designation H0N1 (where H is hemagglutinin and N is neuraminidase). The H0N1 subtype persisted until 1947, when a major antigenic shift generated a new subtype, H1N1, which supplanted the previous subtype and became prevalent worldwide until 1957, when H2N2 emerged. The H2N2 subtype prevailed for the next decade and was replaced in 1968 by H3N2. Antigenic shift in 1977 saw the re-emergence of H1N1. The most recent antigenic shift, in 1989, brought the re-emergence of H3N2, which remained dominant throughout the next several years. However, an H1N1 strain re-emerged in Texas in 1995, and current influenza vaccines contain both H3N2 and H1N1 strains. With each antigenic shift, hemagglutinin and neuraminidase undergo major sequence changes, resulting in major antigenic variations for which the immune system lacks memory. Thus, each antigenic shift finds the population immunologically unprepared, resulting in major outbreaks of influenza, which sometimes reach pandemic proportions.

ferent strands of single-stranded RNA (ssRNA) associated with protein and RNA polymerase (Figure 17-4). Each RNA strand encodes one or more different influenza proteins.

Three basic types of influenza (A, B, and C), can be distinguished by differences in their nucleoprotein and matrix proteins. Type A, which is the most common, is responsible for the major human pandemics. Antigenic variation in hemagglu-tinin and neuraminidase distinguishes subtypes of type A influenza virus. According to the nomenclature of the World Health Organization, each virus strain is defined by its animal host of origin (specified, if other than human), geographical origin, strain number, year of isolation, and antigenic description of HA and NA (Table 17-2). For example, A/Sw/Iowa/ 15/30 (H1N1) designates strain-A isolate 15 that arose in swine in Iowa in 1930 and has antigenic subtypes 1 of HA and NA. Notice that the H and N spikes are antigenically distinct in these two strains. There are 13 different hemagglutinins and 9 neu-raminidases among the type A influenza viruses.

The distinguishing feature of influenza virus is its variability. The virus can change its surface antigens so completely that the immune response to infection with the virus that caused a previous epidemic gives little or no protection against the virus causing a subsequent epidemic. The anti-genic variation results primarily from changes in the hemag-glutinin and neuraminidase spikes protruding from the viral envelope (Figure 17-5). Two different mechanisms generate antigenic variation in HA and NA: antigenic drift and anti-genic shift. Antigenic drift involves a series of spontaneous point mutations that occur gradually, resulting in minor changes in HA and NA. Antigenic shift results in the sudden

Matrix protein Lipid bilayer

Nucleocapsid Hemagglutinin

Neuraminidase

Nucleocapsid Hemagglutinin

Neuraminidase

Neuraminidase And

Nanometers

Nanometers

FIGURE 17-4

Schematic representation of influenza structure. The envelope is covered with neuraminidase and hemagglutinin spikes. Inside is an inner layer of matrix protein surrounding the nucleocapsid, which consists of eight ssRNA molecules associated with nucleopro-tein. The eight RNA strands encode ten proteins: PB1, PB2, PA, HA (hemagglutinin), NP (nucleoprotein), NA (neuraminidase), M1, M2, NS1, and NS2.

Some influenza A strains and their hemagglutinin (H) and neuraminidase (N) subtype

Species

Species

Human

Swine

Some influenza A strains and their hemagglutinin (H) and neuraminidase (N) subtype

Virus strain designation

A/Puerto Rico/8/34

A/Fort Monmouth/1/47

A/Singapore/1/57

A/Hong Kong/1/68

A/USSR/80/77

A/Brazil/11/78

A/Bangkok/1/79

A/Taiwan/1/86

A/Shanghai/16/89

A/Johannesburg/33/95

A/Wuhan/359/95

A/Texas/36/95

A/Hong Kong/156/97

A/Sw/Iowa/15/30 A/Sw/Taiwan/70

Antigenic subtype

Horse (equine) A/Eq/Prague/1/56 A/Eq/Miami/1/63

H0N1 H1N1 H2N2 H3N2 H1N1 H1N1 H3N2 H1N1 H3N2 H3N2 H3N2 H1N1 H5N1

H1N1 H3N2

H7N7 H3N8

Antigenic shift is thought to occur through genetic reas-sortment between influenza virions from humans and from various animals, including horses, pigs, and ducks (Figure 17-6b). The fact that influenza contains eight separate strands of ssRNA makes possible the reassortment of the RNA strands of human and animal virions within a single cell infected with both viruses. Evidence for in vivo genetic reassortment between influenza A viruses from humans and domestic pigs was obtained in 1971. After infecting a pig simultaneously with human Hong Kong influenza (H3N2) and with swine influenza (H1N1), investigators were able to recover virions expressing H3N1. In some cases, an apparent antigenic shift may represent the re-emergence of a previous strain that has remained hidden for several decades. In May of 1977, a strain of influenza, A/USSR/77 (H1N1), appeared that proved to be identical to a strain that had caused an epidemic 27 years earlier. The virus could have been preserved over the years in a frozen state or in an animal reservoir. When such a re-emergence occurs, the HA and NA antigens expressed are not really new; however, they will be seen by the immune system of anyone not previously exposed to that strain (people under the age of twenty-seven in the 1977 epidemic, for example) as if they were new because no memory cells specific for these antigenic subtypes will exist in the susceptible population. Thus, from an immunologic point of view, the re-emergence of an old influenza A strain

Birds

A/Fowl/Dutch/27 H7N7

A/Tern/South America/61 H5N3

A/Turkey/Ontario/68 H8N4

A/Chicken/Hong Kong/258/97 H5N1

Between pandemic-causing antigenic shifts, the influenza virus undergoes antigenic drift, generating minor antigenic variations, which account for strain differences within a subtype. The immune response contributes to the emergence of these different influenza strains. As individuals infected with a given influenza strain mount an effective immune response, the strain is eliminated. However, the accumulation of point mutations sufficiently alters the antigenicity of some variants so that they are able to escape immune elimination (Figure 17-6a). These variants become a new strain of influenza, causing another local epidemic cycle. The role of antibody in such immunologic selection can be demonstrated in the laboratory by mixing an influenza strain with a monoclonal antibody specific for that strain and then cultur-ing the virus in cells. The antibody neutralizes all unaltered viral particles and only those viral particles with mutations resulting in altered antigenicity escape neutralization and are able to continue the infection. Within a short time in culture, a new influenza strain can be shown to emerge.

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PB2 PB1 PA NP HA1 NA M1 M2 NS1 NS2 Viral proteins

FIGURE 17-5

Amino acid sequence variation in 10 influenza viral proteins from two H3N2 strains and one H1 N1 strain. The surface glycoproteins hemagglutinin (HA1) and neuraminidase (NA) show significant sequence variation; in contrast, the sequences of internal viral proteins, such as matrix proteins (M1 and M2) and nucleopro-tein (NP), are largely conserved. [Adapted from G. G. Brownlee, 1986, in Options for the Control of Influenza, Alan R. Liss.]

humoral responses, CTLs can play a role in immune responses to influenza.

Human influenza

Swine influenza

Human influenza

Swine influenza

FIGURE 17-6

Two mechanisms generate variations in influenza surface antigens. (a) In antigenic drift, the accumulation of point mutations eventually yields a variant protein that is no longer recognized by antibody to the original antigen. (b) Antigenic shift may occur by re-assortment of an entire ssRNA between human and animal virions infecting the same cell. Only four of the eight RNA strands are depicted.

FIGURE 17-6

Two mechanisms generate variations in influenza surface antigens. (a) In antigenic drift, the accumulation of point mutations eventually yields a variant protein that is no longer recognized by antibody to the original antigen. (b) Antigenic shift may occur by re-assortment of an entire ssRNA between human and animal virions infecting the same cell. Only four of the eight RNA strands are depicted.

can have the same effect as an antigenic shift that generates a new subtype.

HOST RESPONSE TO INFLUENZA INFECTION

Humoral antibody specific for the HA molecule is produced during an influenza infection. This antibody confers protection against influenza, but its specificity is strain-specific and is readily bypassed by antigenic drift. Antigenic drift in the HA molecule results in amino acid substitutions in several antigenic domains at the molecule's distal end (Figure 17-7). Two of these domains are on either side of the conserved sialic-acid-binding cleft, which is necessary for binding of virions to target cells. Serum antibodies specific for these two regions are important in blocking initial viral infectivity. These antibody titers peak within a few days of infection and then decrease over the next 6 months; the titers then plateau and remain fairly stable for the next several years. This antibody does not appear to be required for recovery from influenza, as patients with agammaglobulinemia recover from the disease. Instead, the serum antibody appears to play a significant role in resistance to reinfection by the same strain. When serum-antibody levels are high for a particular HA molecule, both mice and humans are resistant to infection by virions expressing that HA molecule. If mice are infected with influenza virus and antibody production is experimentally suppressed, the mice recover from the infection but can be reinfected with the same viral strain. In addition to

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