Influenza viruses

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1. History of influenza viruses

In the past, avian influenza viruses were believed to be replicated poorly in humans and other mammals, as there was no convincing evidence of non avian infections by avian influenza virus. However, since 1997 there have been repeated cases of human infection by avian H9N2 and H5N1 influenza viruses in Southern China, Thailand Vietnam and Indonesia. Recently H1N1 (swine flu) is added to the list of highly pathogenic influenza viruses causing outbreaks in humans [1]. Avian influenza virus has raised the concerns for public health not just locally but also posting a pandemic threat to the whole world. Under the circumstance posted by avian influenza outbreak, investigations for all aspects of influenza activity should be broadened and encouraged.

H5N1 influenza A infections have been reported in several mammalian species such as monkeys, mice, pigs, ferrets, domestic cats as well as tigers and Leopards [2]. In south China region, H5N1, H6N1 and H9N2 have become established in the poultry population since mid-1990. Influenza virus is ubiquitous among aquatic bird species. Phylogenetic studies revealed that there are multiple lineages of influenza A viruses co-circulating in shorebirds in North America and other different geographical regions at the same time. Periodically, influenza A viruses are transmitted to other species and establish continual infections in those hosts [3].

2. General introduction of Structure of influenza virus

All avian influenza viruses belong to the Influenza virus A genus of the Orthomyxoviridae family and are enveloped, negative-strand, segmented RNA viruses. Virus particles are usually spherical and approximately 100 nm in diameter [4]. The AIV genome consists of eight RNA segments that range in size from 890 to 2341 bases and code for 11 known proteins [5] (Table 1) (. 1). Influenza viruses produce 11 viral proteins that can be divided into three main categories: the surface proteins, the internal proteins, and nonstructural proteins that are not packaged in the virus particle [6]. The viral particle contains three surface proteins: the HA, neuraminidase (NA), and matrix 2 (M2) proteins The internal proteins include the three polymerase proteins, PA, PB1, and PB2, the nucleoprotein, the matrix 1 (M1), and the nonstructural protein 2 (NS2). The nonstructural protein 1 (NS1) is the only protein that is not packaged into the virus particle, although it is produced in large quantities in infected cells [6]. The surface proteins are the only antigens capable of inducing neutralizing antibody and therefore a protective immune response [7]. Both the HA and NA proteins have high sequence and antigenic differences, and the genes have been separated into 16 different HA and nine different NA subtypes [8]. The different subtypes are characterized by antibody raised to one virus being able to neutralize other viruses of the same HA or NA subtype, but do not cross neutralize viruses of different HA and NA subtypes. Influenza viruses, because of the variation and the importance of the different subtypes, are usually characterized by the HA and NA subtypes [6].

Life cycle of influenza virus

During the infectious cycle, virus particles, bound to cell surface sialic acid, are internalized by receptor-mediated endocytosis and viruses possessing cleaved HA undergo fusion with the endosomal membrane [9] at low pH~5.0. Cleavage of HA is an absolute requirement for infectivity and the nature of the HA cleavage site is an important virulence determinant for influenza viruses [8] [6]. Cleavage efficiency of HA varies depending on the presence of single or multiple basic residues at the cleavage site of HA1 and HA2 and the plasminogen binding ability of NA [6]. Viruses containing HA with a single positive charge at the cleavage site can be cleaved by specific enzymes such as tryptase Clara present in the lungs, whereas HA containing multiple basic residues at the cleavage site are cleaved ubiquitously by proteases [10].

The M2 ion channel opens up in the acidic pH of the endosome, acidifies the internal virion core, and thereby facilitates the release of vRNP from M1 into the cell cytoplasm. M1-free vRNP is then imported into the nucleus through nuclear pores using nuclear transport signals of NP [11]. Inside the nucleus, vRNP undergoes transcription (mRNA synthesis) and replication (complete positive-sense complementary RNA (cRNA), vRNA minus strands, and vRNP synthesis. Progeny vRNPs, made inside the nucleus, are exported out of the nucleus into the cytoplasm with the help of M1 and NEP [12]. Eventually, the envelope proteins (HA, NA, M2), matrix protein (M1) and vRNP (containing vRNAminus-strand, NP, 3P proteins, and NEP) are transported to the assembly site on the plasma membrane where virus particles bud and are released into the outside environment [6]

3. Topological and chronological information about highly pathogenic avian influenza viruses (HPAI)

Influenza A viruses can be divided into subtypes on the basis of the possession of one of 16 antigenically distinct haemagglutinin (HA) antigens (H1 to H16) and one of nine neuraminidase (NA) antigens (NI to N9) [8]. Another way of classification is to divide influenza viruses into two distinct groups on the basis of their ability to cause disease. The very virulent viruses classified as highly pathogenic avian influenza (HPAI), which may result in flock mortality as high as 100% while other viruses cause a much milder disease consisting primarily of mild respiratory disease, depression and egg production problems in laying birds are classified as low pathogenic avian influenza (LPAI) [13].

HPAI was considered a rare disease however, there has been an increase of the number of LPAI and HPAI outbreaks caused by H5, H7and H9 viruses in recent years. The reason for this increase in the number of outbreaks could be linked to the ecology of the virus as well as to the development of densely populated poultry areas, in which biosecurity measures are difficult to implement and retain. Some of these outbreaks have had a great economic impact on the poultry industry [13].

The emergence of H5N1 viruses in Asia since 1996 was a key determinant of the following epidemics. Highly pathogenic avian influenza (HPAI) H5N1 has been reported in several Asian countries including Cambodia, China, Indonesia, Japan, Korea, Laos, Pakistan, Taipei, Thailand and Vietnam[14]. The catastrophic influenza pandemic of 1918, caused by an H1N1 virus, killed 20 to 40 million people. Pandemics caused by the Asian influenza A virus (H2N2) in 1957 and the Hong Kong virus (H3N2) in 1968 indicated that southern China is a hypothetical influenza epicenter [15].

5. Importance of Surveillance and epidemiological surveys for possible global outbreak

Influenza A did trouble the whole world from hot-humid Southeast Asia to cold-freezing Alaska and at least caused 3 severe pandemics in the 20th century [16].

During the past few years, several subtypes of avian influenza A including H5N1, H7N7, H9N2, and possibly H7N3 have been reported to be capable of infecting humans [17]. In 1997, the highly pathogenic avian influenza, H5N1 subtype was isolated from an infected human in Hong Kong, demonstrating direct transmission of the avian influenza virus to humans. A significant re-emergence of highly pathogenic avian influenza (HPAI) H5N1 has been reported in several Asian countries including Korea, Japan, Taipei, Cambodia, Laos, Pakistan, China, Indonesia, and Thailand, with additionally confirmed cases of human death in Vietnam [18]

It can be postulated that H5N1 viruses will continue to circulate in Asia and mutate, and the emergence of new reassortant H5N1 viruses cannot be ruled out. However, the implementation of effective control measures, coupled with enhanced programmes for the surveillance and diagnosis of infection, will help to reduce the risks to animal and human health. Uninfected countries will remain susceptible to the entry of disease from infected areas, and increased vigilance, effective biosecurity and quarantine controls must be maintained to reduce this risk.

Continuous global surveillance of influenza is of key importance. World Health organization (WHO) has a network of 112 National Influenza Centers that monitors influenza activity and isolates influenza viruses in all continents. National Influenza Centers report the emergence of an “unusual” influenza virus immediately to the WHO Global Influenza Programme. Rapid detection of unusual influenza outbreaks, isolation of possible pandemic viruses and immediate alert to the WHO system by national authorities is decisive for mounting a timely and efficient response to pandemics.

1 Structure of influenza A virus. (A) Diagram of the virion. Two types of surface glycoproteins are shown: HA predominates and is evenly distributed over the virion, while NA occurs in patches. Inside the matrix core are eight segments of single stranded negative sense RNA encapsidated by NP in the form of RNP, which occurs in helix (modified from Webster, 2001). (B) Electron micrograph of A/WSN/33 (H1N1). The virion appears spherical and possesses glycoprotein spikes on the surface [19]

Table.1 Gene products of influenza virus

Segment Number*

Nucleotide length

Gene product(s)





RNA transcription




RNA transcription and replication


Inactivate immune cells




RNA replication




Attachment and fusion glycoprotein




Major nucleocapsid structural component




Receptor destroying enzyme




Membrane matrix protein


Membrane ion channel protein




Nuclear export of viral mRNA


Production of influenza viruses with intact RNA genome

*Gene segments are numbered in order of decreasing molecular weight.

**PB1-F2 is a novel protein suggested by Chen et al., 2001 [20].