Influenza A virus

Influenza virus family, or Orthomyxoviridae, comprises of the three known types: Type A, B and C, of which only influenza A virus is capable of infecting birds, but all three types are known to infect humans. Influenza Type A also known as Avian flu comes in subtypes depending on the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) and it further divides into the specific strains depending on the levels of pathogenicity and structural variation

Wild birds are natural hosts of the virus and as opposed to the domesticated kind (chicken) do not become sick when infected. Type A is also categorized into groups of low and called LPAI and [[avian influenza virus, high pathogenicity| HPAI]] accordingly. Most avian flu viruses are considered to be LPAI and associated with very mild cases of disease in birds, while HPAI types cause severe symptoms and death in those animals. LPAI type is capable of evolving into HPAI type. THere are cases of HPAI virus such as H5N1 infect humans with severe symptoms and cause no illness among ducks (host).

Structure

Influenza A virus uses RNA in its propagation, which is enclosed in the capsid. Inside of the capsid the so called internal protein is residing in the form of transcriptase complex (PB1, PB2, PA, NP) that would under favorable conditions lead to a formation of polymerase enzyme for virus particle assembly. Matrix protein surrounds the nucleocapsid and is responsible for maintaining virus' integrity by communicating with the external lipid envelope. The lipid coat has a very important role because it carries the glycoproteins NA (neuraminidase) and HA (hemagglutinin) which are necessary tools virus uses to enter its host.

Replication

The replication of the virus usually begins when particle finds receptors on the host cell that are allowing attachment, Influenza A virus requires terminal sialic (neuraminic) acid residues on the oligosaccharide chains of the infected cells. After the proper attachment cell is stimulated to uptake the virus during the endocytosis. In this process the lipid envelope and matrix is digested and lowering of the pH causes HA protein to transform in a way that permits nucleocapsid with RNA and enzymatic proteins to travel to the host's nucleus (Very low PH does not affect nucleocapsid). In the nucleus viral mRNA is produced and introduced to the replicatory system of the host which after that event is factoring viral progeny. In the next step nucleocapsids are reformed and it travels towards the plasma membrane where NA and HA antigen proteins will be inserted. Release of the mature virons by exocytosis occurs and new cells are infected.

Epidemiology

The major characteristic of the influenza A virus is its antigenic variability of hemagglutinin HA and neuraminidase NA which means virus is in the process of dynamic and continous evolvment which makes protection very difficult. Type A virus uses two ways of change: antigenic shift and drift. During the drift specific point mutations cause alterations in the HA and NA protein structures which make impossible for the host to build immunity and use antibodies during the infection caused by the altered strain. The drift is known to be more common for HA protein and shift for NA. During the antigenic shift the major change like mixing of the subtypes or cross-species move (during the process of the genetic reassortment), causes the formation of the completely novel subtype that carries surface proteins derived from either or both "parent" subtypes. Because of that, new virus may be able to invade new host it was not capable of invading previously. All studied world influenza pandemics were demonstrated to be the result of the process of genetic reassortment (shift and drift).

Virulence of the type A is multifactorial. HA protein variation and NS (non-structure) protein variation plays a role. NS can inhibit host interferon induced anti viral protection and also downregulate appoptosis (one of the known organism's way of protecting itself) and prolonging viron production increasing the severity of infection.

Classification of infection

Influenza Type A can infect wide range of animals like birds, pigs, horses and also humans among others. Those viruses are subdivided depending on their structure (hemagglutinin and neuraminidase), for example H7N2 means that infection is caused by the strain containing hemagglutinin with type 7 protein and neuraminidase type 2. Overall, there are 16 HA types and 9 NA known so far, and they are animal specific. Influenza Type A that is capable of infecting both humans and birds is classified as follows:

• Influenza A H5: nine subtypes are known, HPAI status currently circulating Asia and Europe documented in humans (H5N1), causes severe illness or death.
• Influenza A H7: nine subtypes are known, LPAI (H7N2,H7N7) and HPAI (H7N3,H7N7) status, infections in humans are rare but can occur after direct contact contact with infected birds, upper respiratory symptoms mild to severe and fatal in humans.
• Influenza A H9: nine subtypes are known, rarely infect humans and only in LPAI form.

HUMAN INFECTIONS AND RISKS

Avian influenza usually does not infect humans but rare cases are known and are the result of the direct contacts with the infected animals. In humans the disease poses itself as an eye infection, pneumonia or results in death. Cases of H5N1 subtype infections occurred in Asia, Africa, the Pacific, Europe and the Near East. The only reported case of chicken infections in Texas in 2004 is known and without the human transmission as reported by the

World Organization for Animal Health. Other confirmed instances:

• H7N7 United Kingdom, 1996: human, eye infection, full recovery, contact with ducks.
• H5N1 Hong Kong, 1997: 18 people hospitalized, 6 died, contact with live poultry (market)
• H9N2 China 1999: several human flu like infections reported, full recoveries.
• H7N2 Virginia, 2002: poultry farm infection, one human with flu like symptoms, recovered
• H5N1 China, 2003: 2 human infections, fatal.
• H7N7 Netherlands, 2003: 89 poultry farm workers infected, mild cases, flu like, one death
• H7N2 New York, 2003: 1 human, flu like symptoms, recovered
• H5N1 China, Thailand, Vietnam, 2004: severe and fatal 50 human infections, 36 deaths.
• H5N1 Cambodia, China, Indonesia,2005: severe infection, 98 cases, 43 deaths
• H5N1 Azerbaijan, Cambodia, China, Egypt, Djibouti, Iraq, Turkey, Thailand, Indonesia 2006; 115 human cases and 79 deaths.
• H5N1 Cambodia, China, Egypt, Indonesia, Laos, Myanmar, Nigeria, Pakistan, Vietnam 2007: severe and fatal infections, 86 human cases and 59 deaths.
• H7N2 United Kingdom, 2007: four hospitalized cases with flu like illnesses.
• H9N2 Hong Kong, 2007: one case of mild flu like symptoms

DIAGNOSIS AND VACCINATION

Avian influenza is diagnosed by analysis of the swab of the infected person. In United States FDA cleared the test in 2006. It is called Influenza A/H5 (Asian Lineage) Virus Real -Time Reverse Transcription--Polymerase Chain Reaction Primer and Probe Set. This set is designed to detect the presence of the highly pathogenic Asian lineage H5 subtype viruses. Since most of the severe and fatal cases in the world are reported to be H5 strains the earliest detection is crucial among patients with severe respiratory infection combined with environmental risks of exposure to birds. Such testing is used on a case-by-case basis

The treatment of symptoms is challenging since known antiviral medications like amantadine and rimantadine show no results. Recently, the new drugs has been developed based on the neuramindase NA inhibitor particles that disable virus' ability to release own copies from the infected cell. Those drugs are: Zanamivir which is in the form of dehydrated neuraminic acid analog, Oseltamivir is similar but has cyclohexene ring and polyglycerol moiety.

The vaccine against Type A H5N1 exists and is kept in U.S. Strategic National Stockpile. It is not distributed because the human to human transmission is not proven yet.