Influenza A virus

INTRODUCTION

Influenza virus family comprises of the three known types: Type A, B and C and it is called

Orthomyxoviridae. Only Type A 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 high

pathogenicity called LPAI and 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 maintaing 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 occured 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 reprted, 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 challanging since known antiviral medications like amantadine

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 simmilar 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.

Refernces:

http://www.cdc.gov

http://www.who.int

http://www.hhs.gov

http://www.osha.gov

R.Jennigs, R.C. Read, "Influenza: Human and Avian" The Royal Society of Medicine Press

Limited, 2006, 2nd edition, London.