Antiviral Drugs. General Characteristics of Viruses. Depending on one's viewpoint, viruses may be regarded as exceptionally complex aggregations of nonliving chemicals or as exceptionally simple living microbes.
The virion is generally rounded but may be long and filamentous.A single-stranded RNA genome is closely associated with a helical nucleoprotein (NP), and is present in eight separate segments of ribonucleoprotein (RNP), each of which has to be present for successful replication. The segmented genome is enclosed within an outer lipoprotein envelope. An antigenic protein called the matrix protein (MP 1) lines the inside of the envelope and and is chemically bound to the RNP. The envelope carries two types of protruding spikes. One is a box-shaped protein, called the neuraminidase (NA) (pink rectangles on the surface), of which there are nine major antigenic types, and which has enzymic properties as the name implies.
The other type of envelope spike is a trimeric protein called the haemagglutinin (HA) (illustrated on the left)of which there are 13 major antigenic types. The haemagglutinin functions during attachment of the virus particle to the cell membrane, and can combine with specific receptors on a variety of cells including red blood cells.The lipoprotein envelope makes the virion rather labile - susceptible to heat, drying, detergents and solvents.
Haemagglutinin: A substance, such as an antibody, that causes agglutination of red blood cells.
Agglutination: The clumping together of red blood cells or bacteria.
Receptor-bound viruses are taken into the cell by endocytosis. In the low pH environment of the endosome, RNP is released from MP1, and the viral lipoprotein envelope fuses with the lipid-bilayer of the vesicle, releasing viral RNP into the cell cytoplasm, from where it is transported into the nucleus. New viral proteins are translated from transcribed messenger RNA (mRNA). New viral RNA is encased in the capsid protein, and together with new matrix protein is then transported to sites at the cell surface where envelope haemagglutinin and neuraminadase components have been incorporated into the cell membrane. Progeny virions are formed and released by budding. The cell does not die (at least not initially).
Flu is one of a rare few viruses that has its genome in separate segments (eight). - This increases the potential for recombinants to form (by interchange of gene segments if two different viruses infect the same cell), and may contribute to the rapid development of new flu strains in nature - can also be duplicated in the laboratory (used for making vaccine strains). Avian and human strains recombining in pigs in the Far East may permit virulent human strains to evolve.
CLASSIFICATION of virus STRAINSIs done on the basis of antigenicity of NP (nucleoprotein) and MP (matrix protein) into three main groups: Influenza A -HA undergoes minor and occasional major changes - very important.- NA some variation.Influenza B) Undergoes relatively slow change in HA with time. Known only in man.Influenza C) Uncommon strain, known only in man.
Camp Devens is near Boston, and has about 50,000 men, or did have before this epidemic broke loose. It also has the Base Hospital for the Div. of the N. East. This epidemic started about four weeks ago, and has developed so rapidly that the camp is demoralized and all ordinary work is held up till it has passed. All assembleges of soldiers taboo.These men start with what appears to be an ordinary attack of LaGrippe or Influenza, and when brought to the Hosp. they very rapidly develop the most viscous type of Pneumonia that has ever been seen. Two hours after admission they have the Mahogany spots over the cheek bones, and a few hours later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the coloured men from the white. It is only a matter of a few hours then until death comes, and it is simply a struggle for air until they suffocate. It is horrible. One can stand it to see one, two or twenty men die, but to see these poor devils dropping like flies sort of gets on your nerves. We have been averaging about 100 deaths per day, and still keeping it up. There is no doubt in my mind that there is a new mixed infection here, but what I dont know.
Copy of original letter found in Detroit in 1959
Camp Devens, Mass.Surgical Ward No 1629 September 1918(Base Hospital)
This constant antigenic change down the years means that new vaccines have to be made on a regular basis.
New influenza strains spread rapidly in children in schools and in places where people crowd together. Influenza epidemics may cause economically significant absenteeism.
Amantadine · Oseltamivir · Peramivir · Rimantadine · Zanamivir
Aciclovir · Cidofovir · Docosanol · Famciclovir · Foscarnet · Fomivirsen · Ganciclovir · Idoxuridine · Penciclovir · Trifluridine · Tromantadine · Valaciclovir · Valganciclovir · Vidarabine
NRTIsZidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir · Tenofovir
Nevirapine · Efavirenz · Delavirdine
PIsSaquinavir · Indinavir · Atazanavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir · Tipranavir
Other antiviral agents
Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine
The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named zanamivir and oseltamivir that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.
Both these drugs are effective against the known strains of H5N1 in mouse models although Tamiflu has been disappointing in recent real world use in human H5N1 infection due to 1. delays in treatment and 2. the emergence of resistance. Relenza has not yet been tried in human H5N1 infection.
Most attention has been given to oseltamivir (Tamiflu) because it is a tablet, which is easy to administer. Zanamavir (relenza) is administered as a dry powder inhaler much like some asthma inhalers. An intravenous version of Relenza has been administered to volunteers under study conditions but it is not yet approved or in production. Both drugs can be used to treat influenza; they are also both approved for the prevention of influenza. These drugs are also effective against all strains of influenza A, unlike vaccines which are specific only to the strain for which they were designed. Both medications are well tolerated with few side effects, although there is concern over the possibility of psychological effects of Tamiflu and there may be occasional problems with asthmatics who use Relenza.
Neuraminidase inhibitors must be taken within 48 hours—preferably within 36 hours—of the onset of flu symptoms. They do not ‘kill’ the flu virus but merely slow the virus replication down to a level where the immune system can more easily destroy it. Thus they can reduce the severity and duration of a flu illness.