Influenza Virus

Family: - Orthomyxovirus Disease Influenza A virus causes worldwide epidemics (pandemics), Influenza B causes major outbreaks of influenza and Influenza C causes mild respiratory infections but does not cause outbreaks of influenza. Important Properties It is composed of a segmented single stranded RNA genome, a helical nucleocapsid and an outer lipoprotein envelope. The virion contains an RNAdependent RNA polymerase which transcribes the negative polarity genome into mRNA. The genome is not infectious. The envelope is covered with two different types of spikes, a hemagglutinin and a neuraminidase. Function of hemagglutinin is to bind to the cell surface receptor (neuraminic acid and sialic acid). This is the basis of a diagnostic test called the hemagglutinin inhibition test. The neuraminidase cleaves neuraminic acid to release progeny virus from the infected cell. Hemagglutinin functions at the beginning of infection while neuraminidase functions at the end. Neuraminidase also degrades the protective layer of mucus in the respiratory tract. This enhances the ability of the virus to infect the respiratory epithelium. The virulence of the viruses is maintained by the ability to change the antigenicity of the hemagglutinin and neuraminidase proteins. This contributes to the ability to cause worldwide pandemics of influenza A. There are two types of antigenic changes: 1) antigenic shift which are major changes based on the reassortment of segments of the genome RNA and 2) antigenic drift which are minor changes based on mutations in the genome RNA. Influenza virus has two matrix proteins M1 and M2. M1 resides between the internal nucleoprotein segments and the envelope and provides structural integrity. The M2 protein provides an ion channel between the interior of the virus and the external milieu. It plays an essential role in the uncoating of the virion. It transports protons which disrupts the envelope. There are 2 types of antigens: - Group-specific antigens and Type-specific antigens. Group-specific antigens include the internal ribonucleoprotein and it distinguishes influenza A, B and C. hemagglutinin and neuraminidase are the typespecific antigens located on the surface. Antibody against the hemagglutinin neutralizes the infectivity of the virus. Antibody against the neuraminidase does not neutralize infectivity but does reduce disease by decreasing the amount of virus released from the infected cell and thus reducing spread. Animals are the sources of RNA segments for Influenza A in antigenic shifts. E.G: if avian flu and human virus infect same cell then antigenic shift may occur resulting in a new strain that can cause an epidemic. For Influenza B there are no

animal sources and therefore do not undergo antigenic shifts. But they undergo enough antigenic drifts so that each year the new strains have to be added to the vaccines. Also Influenza A and B do not have any common antigens.

Summary of Replication Cycle The virus is absorbed into the cell when the viral hemagglutinin interacts with sialic acid receptors on the cell surface. The virus then enters the cell in vesicles called endosomes and uncoats. This is facilitated by low pH within the endosome. Protons pass through the ion channel formed by the M2 protein into the interior of the virion. The envelope is disrupted and the nucleocapsid enters the nucleus where the genome RNA is transcribed. The RNA polymerase transcribes the 8 segmented RNA genome into 8 mRNA. Most of them leave the nucleus into the cytoplasm where viral proteins are synthesized. Some remain in the nucleus where new negative sense RNA genomes are synthesized for progeny viruses. Two newly synthesized proteins NP protein and matrix protein bind to the progeny RNA genome in the nucleus and moves into the cytoplasm. Helical ribonucleoprotein is assembled in the cytoplasm. The virion is released from the cell by budding at the site where hemagglutinin and neuraminidase are located. Neuraminidase cleaves neuraminic acid on the cell surface at the site of budding of progeny viruses. Influenza, hepatitis delta virus and retroviruses are the only RNA viruses where the replication occurs in the nucleus. Transmission & Epidemiology The virus is transmitted by airborne respiratory droplets. The ability of Influenza A is the ability to change antigenicity of hemagglutinin and neuraminidase. Pathogenesis & Immunity Infections are limited to the respiratory tract because the proteases to cleave the hemagglutinin are present only there. Severe myalgia is due to circulating cytokines in the blood. There is also necrosis of the superficial epithelium of the respiratory tract. Complications are influenza and bacterial pneumonia. Immunity depends on the secreted IgA in the respiratory tract. IgG is also present but is less protective. Cytotoxic T cells also play a protective role. Clinical Findings There is an incubation period of 24-48 hours followed by fever, myalgia, headache, sore throat, and cough. Vomiting and diarrhea are rare. Symptoms usually disappear within 4-7 days. Reyes syndrome may occur in children and is life threatening. It is characterized by encephalopathy and liver degeneration. Aspirin given for fever is the cause of pathogenesis for Reyes syndrome. Treatment

Main medication is amantadine for both prevention and treatment but 90% of the strains are resistant. The drug blocks the M2 ion channel there by inhibiting the uncoating of the virus. Resistance to the drug is due to point mutations which codes for the M2 ion channel. It is only effective against Influenza A and not B. Rimantadine is a derivative of amantadine. Another two drugs used are oseltamvir and zanamivir. They act by inhibiting the neuraminidase n reducing the number of viruses released from the infected cells. They are effective against both A and B strains. They are proven to reduce symptoms within 1 2 days. For effective treatment they should be administered within 48 hours of onset of symptoms.

Prevention Main mode of prevention is by vaccination. Usually each vaccine has 2 strains of A and 1 strain of B. the common vaccine used is killed vaccine with purified protein subunits of the virus (hemagglutinin and neuraminidase). It is administrated intramuscularly. In 2003 a new vaccine was approved. It is a live vaccine containing temperature sensitive mutants of influenza A and B. it works at 33C (nasal mucosa) and is quickly killed at 37C (lower respiratory tract). Advantage of the live vaccine is that the secreted IgA and the titer of IgG are far higher. It is administered as a nasal spray. Drugs are not a substitute for the vaccine.