Influenza Series: Influenza A Virus Updates

Influenza is an acute respiratory disease caused by the influenza virus also commonly known as “flu”. Flu differs from the “common cold,” which is also associated with mild respiratory symptoms, being a more severe form of respiratory infection. Worldwide, about 300,000 to 500,000 people per year die of seasonal flu epidemics and the mortality rate is estimated to be 0.2%. In the United States, about 30,000 to 40,000 peoples succumb to flu every year. Influenza virus infects and damages the mucous membrane of the upper respiratory tract. which otherwise acts to eliminate invading microbes. As a result, secondary bacterial infection to the lower respiratory tract can be incurred. A fatal outcome is caused by secondary bacterial pneumonia infection.

Influenza viruses are part of the family Orthomyxoviridae which comprises three genera (ie, A, B, and C), based on the antigenicity of viral NP and M proteins. Unlike influenza B and C, influenza A can infect not only humans but also birds, pigs, and horses. The influenza virus is an enveloped virus where the outer layer is a lipid membrane which is taken from the host cell in which the virus multiplies. It has three membrane proteins HA, NA, and M2, and a matrix protein M1 just below the lipid bilayer. Also there is ribonucleoprotein core  which consists of 8 viral RNA segments and three proteins: PA, PB1, PB2, and the NEP/NS2 protein. Influenza viruses have a standard nomenclature that includes virus type; species from which it was isolated (if non-human); location at which it was isolated; isolate number; isolate year; and, for influenza A viruses only, HA and NA subtype. Thus, A/Panama/2007/1999(H3N2) was isolate number 2007 of a human influenza A virus taken in the country of Panama in 1999, and it has an HA subtype 3 and an NA subtype 2. While genetically distinct subtypes 16 for HA and 9 for NA have been found in circulating influenza A viruses, only three HA (H1, H2, and H3) and two NA (N1 and N2) subtypes have caused human epidemics.

HA (hemagglutinin) and NA (neuraminidase) are glycoproteins and they determine the subtype of influenza virus. HA and NA are important in the immune response against the virus and antibodies against them may protect against infection. NA protein is an enzyme that is essential for release of progeny virus particles from the surface of an infected cell. NA protein removes sialic acid from glycoproteins, sialic acid is present on many cell surface proteins as well as on the viral glycoproteins. It is also called as the cell receptor to which influenza virus attaches via the HA protein. When the virus particle encounters a cell, it binds the sialic acid-containing receptor and is rapidly taken into the cell before the NA protein can cleave the carbohydrate from the cell surface. NA property for virus production has been exploited to develop new drugs that mimic sialic acid that bind tightly in the active site of the NA enzyme to inhibit viral release.

Mutations in viral RNA and recombinations of RNA from different sources lead to viral evolution. High mutation rates and frequent genetic reassortments of these viruses contribute to the great variability of the HA and NA antigens. The currently 16 HA and 9 NA subtypes of influenza A viruses are identified. Humans are generally infected by viruses of the subtypes H1, H2 or H3, and N1 or N2. Minor point mutations or antigenic drift occur relatively often and it enables the virus to evade immune recognition, resulting in repeated influenza outbreaks during interpandemic years. Influenza viruses can evolve in a gradual way through mutations in the genes that relate to the viral surface proteins HA and NA. These mutations may cause the virus’s outer surface to appear different to a host previously infected with the ancestor strain of the virus. In such a case, antibodies produced by the previous infection with the ancestor strain cannot effectively fight the mutated virus, and disease results. (Hemagglutinin and neuraminidase lend their first initials to flu subtypes. As mutations accumulate in future generations of the virus, the virus “drifts” away from its ancestor strain. Antigenic drift is one reason that new flu vaccines often need to be created for each flu season.

Major changes in the HA antigen or antigenic shift are caused by reassortment of genetic material from different A subtypes. Influenza A (H1N1) virus emerged in 2009 occurred due to antigenic shift. Antigenic shift is a process by which two or more different types of influenza A combine to form a virus radically different from the ancestor strains. The virus that results has a new HA or NA subtype. The antigenic shift may result in global disease spread, or pandemic because humans will have few or no antibodies to block infection. Antigenic shift occurs in two ways, firstly through genetic recombination, or reassortment, when two or more different influenza A viruses infect the same host cell and combine their genetic material. Influenza A viruses can infect birds, pigs, and humans, and major antigenic shifts can occur when these virus types combine. Second, an influenza A virus can jump from one type of organism, usually a bird, to another type of organism, such as a human, without undergoing major genetic change. If the virus mutates in the human host so that it is easily spread among people, a pandemic may result. Antigenic shift produces a virus with a new HA or NA subtype to which humans have no, or very few, pre-existing antibodies. Antigenic shift occur only with influenza A, as it is the only influenza type that can infect a wide variety of animals: humans, waterfowl, other birds, pigs, dogs, and horses. Recombination possibilities, therefore, are very low or nonexistent with influenza B and C.

There have been only two families of FDA-approved direct acting drugs i.e. blockers of M2-mediated ion-channel and neuraminidase inhibitors (NAIs) [1,2]. The M2 blocker is derivative of adamantanes for oral administration including rimantadine and amantadine. These are the first generation anti-influenza drugs prevent the endosomal exit of the vRNP into the cytoplasm. NAIs include Tamiflu, Relenza, Inavir [3]. The NAIs inhibit the release of the virus progeny from the infected cells and the viral spread [4].

Annual vaccination against influenza is also recommended for specific age population [4]. Flu shots may be trivalent (consisting of three strains, one strain each of H1N1 and H3N2 and one IBV strain usually Yamagata lineage) or quadrivalent (four influenza strains, one strain each of IAV H1N1 and H3N2 and one strain each of IBV Yamagata and Victoria lineages) [5]. World Health Organization (WHO) recommends the viruses that are antigenically and genetically matched with the causative viruses of the particular flu season for influenza vaccine inclusion. The recommended candidate vaccine strains are different also for northern and southern hemisphere influenza seasons

In the human history, several catastrophic influenza A pandemics have occurred periodically. Spanish influenza caused by subtype H1N1 during 1918-1919 with an estimated 20–50 million deaths. Asian flu caused by subtype H2N2 in 1957-1958 (~1–4 million mortality), and Hong Kong flu caused by H3N2 in 1968-1969 (~1–4 million deaths). In 1997, avian influenza H5N1 was transmitted from chicken to infect human. Subsequently, it spread to other countries in Asia and other continents causing a high mortality rate, a global health threat, and a huge economic loss [6,7]. In the first decade of this century, the World Health Organization (WHO) declared an influenza pandemic caused by a new H1N1 strain (subsequently named pandemic H1N1-2009, pdm09H1N1). Molecular analysis revealed that the virus contains a genetic combination of H1N1 of the North American and the Eurasian swine lineages [8,9].

Novel anti-influenza agents that are safe and effective against multiple strains with high tolerability to the viral mutations (antigenic drift or shift) is an active area of investigation. Also, the recombinant small antibody fragments to influenza proteins await preclinical and clinical trials towards the application as a novel, broadly effective, and safe anti-influenza agent.


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