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Viruses and what they do -. An overview. Wednesday, August 25, 2010. Viruses (Encyclopedia Britannica). - PowerPoint PPT Presentation

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  • Viruses and what they do -An overviewWednesday, August 25, 2010

  • Viruses (Encyclopedia Britannica)..infectious agents of small size and simple composition that can multiply only in living cells of animals, plants and bacteria. Viruses are obligate parasites that are metabolically inert when they are outside their hosts. They all rely, to varying extents, on the metabolic processes of their hosts to reproduce themselves. The viral diseases we see are due to the effects of this interaction between the virus and its host cell (and/or the hosts response to this interaction).

  • Viral GenomesNucleic AcidDNARNADouble StrandedPositiveNegativeRNADNASingle StrandedDouble StrandedSingle Stranded

  • SS RNA genomesAUG GCA CGAUAC CGU GCUmet ala arg+ve (sense) and -ve (anti-sense) RNA genomes

  • VirioncapsomeresCapsidenvelopedVirus or Virionenvelopecapsidnaked virus particle or Virionherpesadeno

  • Proteins produced by virusesStructural proteinsNon-structural proteins

  • Some viral shapesadenovirusparvoviruspapillomavirus100 nm1 nm = 1 millionth of a mm100 nm = 1 ten thousandth of a mmnaked viruses

  • Some viral shapesherpesvirusparainfluenzavirusinfluenzaviruspoxvirus1 nm = 1 millionth of a mm100 nm = 1 ten thousandth of a mm100 nmEnveloped viruses

  • TaxonomyWhat is it?On what is it based?Is it important?Do I need to remember all the details?International Committee onTaxonomy of Viruses

  • Viruses with ss DNA genomesCircoviridaeParvoviridaeporcine circoviruscanine parvovirus-2feline panleukopenia virusporcine parvovirus (SMEDI)

  • Viruses with ds DNA genomesPoxviridaeAfrican swine fever virusHerpesviridaeAdenoviridaePapovaviridaepapillomavirusesadenovirusesbovine herpesvirus-1,2 porcine cytomegalovirus equine herpesviruses -1,4 african swine fever viruspoxvirusesmalignant catarrhal fever virus

  • Viruses with ds RNA genomesReoviridaeBirnaviridaerotavirusesbluetongue virusafrican horse sicknessinfectious bursal disease (chickens)infectious pancreatic necrosis (salmonid fish)

  • Viruses with +ve RNA genomesPicornaviridaeCaliciviridaeCoronaviridaeArteriviridaeFlaviviridaeTogaviridaefoot and mouth disease virus porcine enterovirusesfeline calicivirusequine arterivirus, PRRSpestiviruses (BVD)coronavirusesequine encephalitis virusesflaviviruses (WNV)

  • Viruses with -ve RNA genomesParamyxoviridaeRhabdoviridaeOrthomyxoviridaeFiloviridaeBunyaviridaeparainfluenza viruscanine distemper virusrespiratory syncytial virusrabies virusvesicular stomatitis virusinfluenzavirusesEbola virusHaantan virusHendra, Nipah viruses

  • Viruses with reverse transcriptaseRetroviridaeHepadnaviridaefeline leukemia virusfeline, bovine immunodeficiency virusesbovine, avian leukosis virusescaprine arthritis-encephalitis virus

  • How new serotypes arise gradual changes in external proteins due to pressure by neutralizing antibodiesAntigenic classification:Serotypes and Groups

  • antibodies to all viral proteinsselective pressureonexternal viral proteinsantibodies to external proteins neutralize virusno selective pressure on internal proteins

  • antibodies to all viral proteinsselective pressureonexternal viral proteinsantibodies to external proteins neutralize virusselective pressure forces selection of virions with slightly different external proteins

  • antibodies to all viral proteinsselective pressureonexternal viral proteinsantibodies to external proteins neutralize virusselective pressure forces slight change in external proteinsvirus, including changed virus passed on to new host

  • process repeated, over time..serum from original catneutralizesneutralizesneutralizesneutralizesdoes not neutralizeNOTE: Only external proteins change. Internal proteins do not change

  • process repeated, over timeserum from original catneutralizesneutralizesneutralizesneutralizesdoes not neutralizenew serotypeNOTE: Only external proteins change. Internal proteins do not changesame serotype

  • Serotype - all isolates of a virus that can be neutralized by a common antiserum are said to belong to the same serotype...because of changes in external protein (internal proteins do not change)

    external proteins are called TYPE SPECIFIC antigensinternal proteins are called GROUP SPECIFIC antigens

  • process repeated, over timenew serotypesame serotypedifferent serotypessame group

  • Groups, types (sero-types), isolates and strainsGroupType -AType - BType - CGroup specific antigenType -A specificantigenType - C specificantigenisolate

  • Group and type specific antigensgroup specific antigentype specific antigennakedvirus(eg FMDV)enveloped virus(eg influenza, FeLV)

  • Serotypes and neutralizing antibody (eg. FMDV)serotypes of FMD virusAOCSAT1SAT2SAT3Asiaantibodies against receptor binding protein of serotype A will neutralize viruses of serotype A but not of serotype Creceptorreceptor binding protein on viral surface

  • example - influenzagroup specific antigentype specific antigenserotype H1serotype H5serotype H7test based on group specific antigen will detect all threevaccination against one serotype will not protect against others

  • Infection of a cell

    StageBiological implicationsHost defensesDrug intervention

  • Distribution of the CCR532 mutation in human populationsfrom PLoS Biology, Nov 2005

  • Errors in replication lead to quasispeciespersistentinfectionmixture of variant viruses(quasispecies)

  • inclusion bodies

  • Release of virusRelease by lysis of cell(cytopathic)

    or by budding (withoutdeath of cell, non-cytopathic)

    **obligate parasites - since viruses rely to varying extents on the host cells metabolic processes it has been difficult to develop anti-viral agents that are specifically targeted to viral mechanisms. The development of antiviral agents has therefore lagged behind the development of anti-bacterial agents (antibiotics). However, in the last few decades much progress has been made and we now have reliable anti-virals against many human pathogens such as HIV, herpesviruses and influenza viruses. None have been approved for veterinary use although some antivirals designed for people can be used (off label) quite effectively to control infections in animals (eg. acylovir or Valacyclovir to control equine herpesvirus type 1).

    The viral diseases we see are due to the effects of this interaction between the virus and the host-cell (and/or the hosts response to this interaction) - cell destruction and/or loss of function. Cell destruction -> inflammation -> cytokines -> clinical signs*simple composition - viruses, in their extracellular state are made up of the genome (nucleic acid, either DNA or RNA), protein and, sometimes, the main structure is surrounded by a lipo-protein envelope.The genome can be either single or double stranded. In the case of RNA it can have either a positive (can function as mRNA) or a negative (must be converted to a positive strand mRNA before translation).In some cases the genome is RNA but must be converted to a DNA copy in the infected cell before virus replication can begin.Cells are less able to proof-read RNA than DNA. RNA viruses are therefore generally more changeable. This leads to phenomenon such as antigenic drift, change in virulence and tissue specificity.**virus made up of protein coat called capsid + genome.capsid - made up of capsomeresCapsid. Capsids, when they contain a genome are sometimes called nucleocapsidsvirion - infectious unitsome viruses are enveloped - in such cases virion is made up of nucleocapsid + envelope since nucleocapsid, by itself would not be infectiousother viruses are nakedenveloped viruses are generally more sensitive to inactivation -> spread by close contact. Naked viruses are more difficult to inactivate. Implications for spread and disinfectants*Structural proteins are proteins that make up the virionFor all viruses these proteins mediate the initial stages of infection - getting the virus into its host cell - attachment to the cell as well as penetration of the cell membrane. For other viruses the virion acts as a tool kit and has proteins for specialized functions such as enzymes needed to begin the program for infection, replicating the genome, modifying the host cell so that it is dedicated to replicating the virus.

    Non-structural proteins - proteins produced in virus-infected cells which are not a part of the infectious virion. Enzymes needed to make precursors of DNA or RNA, DNA or RNA polymerases, proteins that reprogram the host cell and proteins that either suppress the hosts defenses or protect infected cells from the immune system. Non-structural proteins often determine virulence and pathology. For instance, Obenauer and others recently discovered (Science, Jan 26, 2006) that avian influenza viruses (such as H5N1), which often cause severe disease in people, have a non-structural protein that is different from that of flu viruses that have adapted to humans. This difference may allow the avian viruses to activate signaling pathways in human cells leading to cytokine storms which are thought to be responsible for the severe, often fatal disease caused by these viruses. Immune response against non-structural proteins can be used to distinguish between an animal that has been vaccinated with a vaccine containing inactivated virus and one that has been exposed to a disease causing virus (important for diseases such as Foot and Mouth where exposed animals must be culled).*Viruses are too small to be seen by light microscopy. To visualize viruses the sample is stained with metal containing dyes. The dye enters the crevasses of the structures and is excluded from the tightly packed molecules. An electron beam is then shown on the sample. Electron dense areas (impregnated with dyes) show up dark. Areas the electrons can penetrate show up as white.

    The electron microscope is often used as the first step to identifying an unknown virus in a sample. It allows one to identify which family a virus in the sample belongs.**Taxonomy - from tassein (Greek for to classify) or taxis (Gr for order, arrangement) and nomos (law). The science of classifying living things.Viral taxonomy is an attempt to bring order to the large number of viruses discovered in the last eighty years. Based on appearance of virus in EM, structure, type of nucleic acid and genetic homology. It has more practical purposes as well. All members of a group often have similar biological properties. Knowing something about the biological properties of a group sometimes tells you something about how a newly discovered member might behave. For instance, all herpesviruses have the same structure and look the same in electron micrographs. They also all become latent in their hosts and are reactivated periodically. A new member (the Brazilian Mugwump virus) would therefore also be expected to cause recurrent reactivations. Most members of the genus Flavivirus (West Nile Virus) are spread by insects. If a new virus, that has physical and chemical properties of flaviviruses, is discovered the chances are that it is spread by insects as well. Based on - viral genome, morphology, biological properties, serological relationships*******isolate - every time a laboratory isolates and grows a virus and does some basic characterization (identification) that virus is referred to as the isolate. If an isolate is characterized further (serological and biological properties) and is used in experiments it is sometimes referred to as a strain.The term serological property refers to the antigenic characterization of a virus.When a virus infects an animal the animal eventually produces antibodies against all the viral proteins - proteins that lie on the outside of the virion and proteins that are inside the nucleocapsid.Proteins on the outside of the virion allow it to attach and enter host cells and antibody directed against these proteins can neutralize the infectivity of the virion by blocking this process.Serotype - all isolates of a virus that can be neutralized by a common antiserum are said to belong to the same serotype. Since neutralization involves the external proteins of a virion the serotype is dictated by these proteins. For instance, feline leukemia viruses (FeLV) come in one of three serotypes - A, B and C. All FeLv isolates that can be neutralized by Anti-A serum are said to belong to serotype A. Isolates that are not neutralized by Anti-A serum belong to either serotype B or C, and so on.While the external proteins of viruses of different serotypes may be antigenically different, the proteins on the inside may be antigenically similar. For instance the inner proteins of FeLV of all three serotypes are similar and react in immunological tests to antibodies against the inner protein. All viruses that react to antibodies directed against the inner protein are said to belong to the same group. The inner protein is called the group specific antigen while the external proteins are called the type-specific antigens.**implications - vaccination with one serotype or prior infection with one serotype does not protect against infection by another serotype.**Steps in virus infection 1) attachment - a specific interaction between a protein present on the surface of the virion (capsid, or for enveloped viruses - in the envelope) and a molecule on the surface of the host cell. Eg - membrane associated lactase on intestinal epithelial cells are receptors for rotaviruses,CD4 and coreceptor CCR5 are receptors for HIV, sialic acid for influenza viruses. Because the interaction between the virus and the host cell is specific some viruses can only infect particular species or organs (host or tissue specificity). Viruses must change viral protein to alter host-range. Conversely, genetic mutations in host protein can lead to resistance. Eg CCR5D32 mutation in northern European populations and resistance to HIV (see notes for slide - Genetic Resistance). Incidentally the CCD5D32 mutation may not be without cost - a report by Glass et al. in the Jan 23, 2006 issue of the Jn of Exp Med (203:35) report that the mutation is over represented in patients with severe or fatal West Nile Virus disease (1% in normal population vs 4to 8%). The deletion may also make individual more susceptible to severe disease by related viruses (for recent review see Klein, J Inf Dis. 2008, 197:183).

    Attachment is one step which is prevented in the immune animal. Antibodies directed against viral proteins that mediate attachment neutralize viral infectivity.

    2) entry - The act of virus binding to its receptor may trigger the cell to take up the virus. Eg. The binding of Coxsackie B virus to decay accelerating factor (DAF) on epithelial surfaces causes actin rearrangement and stimulates the transfer of the virus into the cell in caveolin vesicles.

    3) Uncoating - The viral genome is released from the nucleocapsid. For some viruses this process can be interrupted (influenza and amantadine).

    4) gene expression - The viral genome is expressed to make non-structural proteins and structural proteins. By exploiting differences between cellular and viral enzymes drugs can be...

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