Viruses Human Disease Chapter 1 Virus an obligatory intracellular parasite that carries a nucleic acid genome enclosed by a protein coat Its genome carries limited information Cannot survive outside the host cell Discovered by A Mayer M Beijerinck D Ivanovsky Enveloped viruses viruses that have additional lipid membrane surrounding the protein coat Virions also called virus particles a virion refers to a physical particle whereas a virus is a more general term Resolution of a microscope ability to distinguish two objects as separate entities Bacteriophages viruses that infect bacterial cells 1 micron 1 micrometer Bacterial and eukaryotic cells have a diameter ranging from 10 100 micrometers A filter with 2 micron sized pores will effectively remove bacterial contamination by trapping them in the filter Nanometer nm Viruses have diameters ranging from 20 100nm the same filter will not remove most viruses Molecules are in the Angstrom range A nanometer nm 10 angstrom Light microscope uses photons can be used to trace real time changes in the host cell caused by an infection Electron microscope uses electrons can be used to visualize a viral particle requirement of a vacuum so it can t image live samples Viral causes Common cold rhinovirus Flu influenza virus Warts human papillomavirus 1 2 4 Cold sores herpes virus Diarrhea enterovirus AIDS HIV Poliomyelitis poliovirus Hemorrhagic fever Ebola dengue SARS coronavirus Chapter 2 Transmembrane protein a protein that spans across the membrane lipid bilayer at least once Viral receptor a cell surface molecule that is bound by a virus to mediate its entry into host cells Tropism the phenomenon that viruses are capable of infecting certain cell types but not others Endocytosis cellular uptake of materials from extracellular space using membrane bound vesicles called endosomes Highly pathogenic avian influenza HPAI virus avian flu virus that has crossed over from waterfowl to domestic birds and causes high rate of death in the latter population General steps of a virus life cycle 1 Entry this includes receptor binding all the way to membrane penetration 2 Replication of viral genomes which requires the expression of replication enzymes 3 Viral assembly and exit which requires the expression of structural proteins Structure of biological membranes Lipid bilayer with embedded transmembrane proteins A barrier that viruses must cross to deliver its genome into the cells Importance of studying viral receptors Elucidation of viral tropism Help predicting viral pathogenesis Reveal drug targets for therapy Identification of HIV receptors Part I A cell surface molecule called CD4 is the primary receptor of HIV o HIV only infects a subset of human T cells that express a cell surface o HIV envelope protein binds to CD4 and blocking of this interaction molecule called CD4 prevents HIV entry o HIV infection selectively depletes CD4 expressing T cells weakening However mouse cells expressing the human CD4 molecule are still not the immune system permissive for HIV entry o CD4 is necessary but not sufficient for entry there is something else Functional cloning Identification of inhibitors Humans naturally lacking this molecule Part II Part III entry Maraviroc also called selzentry is an inhibitor of CCRS a coreceptor for HIV Approved by FDA in 2007 for treatment of HIV infection A successful example of an antiviral strategy called host targeting Four possible routes of viral entry following receptor binding Pore formation at the cell surface neutral pH Membrane fusion at the cell surface neutral pH Pore formation in the endosomes acidic pH Membrane fusion in the endosomes acidic pH Chapter 3 Nucleic acid a polymer made up of repeating units of nucleotides can be either DNA or RNA Semiconservative replication during DNA replication each daughter DNA contains one strand of parental DNA and one strand of new DNA Reverse transcriptase the enzyme that uses RNA as template to produce DNA By in large absent from the host cells and has to be carried in by the virions RNA dependent RNA polymerase the enzyme that uses RNA as a template to produce DNA By in large absent from the host cells it has to be either carried in by the virions or encoded by the viral genome Class Genome Replication Strategy Example Seven types of viral genes I dsDNA DNA DNA VI II ssDNA ss RNA RT DNA DNA RNA RNA RNA RNA RNA RNA RNA DNA RNA IV ss RNA V ss RNA III dsRNA VII dsDNA RT DNA RNA DNA Herpes virus Phage rotavirus Dengue virus Influenza virus HIV Hepatitis B virus There is a lack of a double stranded genome type with one strand of DNA and one strand of RNA These molecules are physically unstable Viruses are successful despite having limited coding capacity in their genomes Host provides much of the service Viral genomes are more efficient in carrying information ex overlapping reading frames The structure of nucleic acids polymers of nucleotides monomers Made up of three parts o A nitrogenous base G A T U C different for different nucleotides giving the nucleotide its name o A pentose 5 carbons sugar different for DNA and RNA o A phosphate group invariable DNA Guanine G Adenine A Thymine T Cytosine C RNA Guanine G Adenine A Uracil U Cytosine C Why do RNA viruses have a much higher mutation rate The enzymes used to copy RNA genomes have low fidelity during replication make more mistakes These include the reverse transcriptase and RNA dependent RNA polymerse The DNA polymerases which the host cell and DNA viruses use have much higher fidelity Reconstructing extinct viruses obtain viral genome sequence and use it to synthesize a man made genome 1 Find preserved viral genome in frozen body tissue 2 Extract RNA and obtain sequence of the complete genome 3 Synthesize genome 4 Grow virus in cell culture 5 Test virus in mice Positive Vs Negative sense RNA genomes Positive sense RNA directly spells out the code for protein translation Negative sense RNA needs to be converted to positive sense RNA via the base pair rule to spell out the code for protein translation As a result negative sense RNA viruses need to carry their own RNA dependent RNA polymerase in their viral particles Chapter 4 Icosahedron by having 20 faces and three types of symmetries 5 fold 3 fold and 2 fold a common shape adopted by viruses It is characterized Packaging signal a piece of viral DNA RNA sequence that is necessary and sufficient for incorporation into virions It is unique for each virus Metastable state a long
View Full Document
Unlocking...