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e-Journal

 

Avian Influenza (Bird Flu)
(Released July 2007)

 
  by Sujata Suri  

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Replication, transcription & translation

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Transcription & Replication (Fig. 5)

The AI virus which contains negative (-) sense RNA as genetic material enters the host cell by adsorption (attachment) to the cell surface. Its hemagglutinin binds with the sialic acid present on glycoprotein receptors of the host. After adsorption, it is internalized as an endosome due to the acidic environment of the host cell.

 

diagram of viral replication
Fig. 5 Influenza A virus replication, transcription and translation

In the cell cytoplasm the virus releases its nucleocapsids that further are transported into the nucleus, where mRNA synthesis and replication occurs. Once it enters the nucleus, viral endonuclease snips off the 5' end of the host capped, methylated mRNA about 13-15 bases from the 5' end. This snipped part of the host mRNA is used as a primer by the virus to synthesize its own mRNA. Next, viral RNA polymerase further extends the primer and makes a complementary (mirror image) plus (+) strand mRNA. Transcription results in 8 primary transcripts /mRNA that are further translated in the cytoplasm. The cells treat the viral mRNA like their normal mRNA and uses them to make copies of viral proteins. These are about ten proteins translated from the 8 mRNA transcripts e.g., hemagglutinin, neuraminidase, PB1, PB2, nucleoprotein, another RNA polymerase complex, 2 matrix proteins and 2 NS proteins.

Replication

RNA replication occurs in the nucleus with the help of viral RNA polymerase (or modified RNA polymerase) that was also involved in transcription . In the same manner, as explained above, the (+) strand of RNA (e.g. cRNA) is synthesized, and is coated with nucleocapsid proteins soon after it is made. This plus strand is then used as a template to synthesize a new negative RNA strand followed by coating with nucleocapsid proteins. These can further serve as templates for replication, mRNA synthesis or packaging into virion particles.

These (-) strand RNA (vRNA) are transported into the cytoplasm, where other viral proteins assemble together and are packaged into virion particles and, on maturity, bud off from the outer cell membrane and infect new cells.

Classification

AI virus belongs to the Order "Mononegavirales" and Family Orthomyxoviridae, and on the basis of their Nucleocapsid and M protein antigens, they are divided into three distinct immunological types: Influenza virus Type A, Influenza virus Type B, and Influenza virus Type C. IA virus subtypes are classified and named according to the types of HA and NA surface proteins. There are 16 types of HA surface proteins (which are named H1, H2, H3 . . . H16) and 9 types of NA surface proteins (which are named N1, N2 . . . N9) . An influenza virus always has one type of HA surface protein and one NA surface protein and it could be of any combination of H and N e.g., H5N1, H7N3, H7N7, H5N2, H5N8 and so on. Within these subtypes, some viruses with slightly different nucleotide sequences are present and are classified into strains. The most virulent form so far reported is H5N1 of Influenza virus.

Influenza virus Type A can be divided into 2 distinct groups on the basis of their ability to cause disease. Highly pathogenic avian influenza (HPAI) can cause up to 100% mortality in birds (Alexander). To date, all outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7. I will mainly focus on Influenza virus Type A, the most virulent human pathogen and cause of all flu pandemics.

Generally, Avian viruses do not infect humans, but they do have potential to cross the "species barrier" and develop into new viral strains that are infectious to humans. Several theories have been put forward to explain the origin of new strains. A few are as follows:

Antigenic Shift

Viruses isolated in the years 1933-46, 1947-56, 1957-67 and from 1968 onwards demonstrated wide antigenic variation, so it is apparent that pandemics are due to the appearance of new influenza A subtypes against which the human population has no immunity. This phenomenon is known as antigenic shift. As immunity to a particular new subtype builds up in the population at large, further epidemics are more limited.

Reassortment

This theory is based on the view that the new virus subtypes are reassortant viruses resulting from dual infection. The 8 ssRNA segments of each strain reassort with each other, producing a new subtype. IA viruses can cross the "species barrier," and pigs are postulated as the most likely "mixing vessel."

avian H3 & human H2 meet in a pig to become human H3
Fig. 6 Reassortment of human H2 with avian H3 virus: e.g., emergence of the H3N2 pandemic virus in 1968.

Antigenic Drift

Though pandemics arise due to antigenic shifts every 10-12 years, smaller epidemics can occur regularly in the intervening years. The viruses isolated from such epidemics showed strain differences when compared in the HAI tests, i.e. although the viruses belong to the same subtype, they do not crossreact completely. These lesser antigenic changes are known as antigenic drift. Antigenic drift can arise due to natural mutation or selection over time.

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