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BIOD29H3 (15)
Lecture

BIOD29 Lecture 1B

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Department
Biological Sciences
Course
BIOD29H3
Professor
Aarti Ashok
Semester
Fall

Description
BIOD29 Pathobiology of Human Disease Lecture 2 January 11, 2012 Continuation of Biology of Viruses Class IA Virus Classification  The study of classification is known as taxonomy.  Emerging pathogens are viruses we haven’t encountered or mutated virus that does not have a name.  Classification is based on many things and can include geometrical information which we will not talk about.  Viruses can have a single stranded genome so it depends on if they have a positive or negative strand.  Baltimore classification system is intuitive and easy to understand.  The ‘sense’ strand is the strand that is equivalent to the mRNA.  Negative stranded RNA genome is bringing in the complimentary strand of RNA and this strand is the mRNA. There is a one-step difference between this and positive stranded RNA.  There are two strands but they almost always have dependent RNA polymerase which uses the negative strand to make the mRNA. Similarity between double stranded and negative stranded. (3 and 2)  Energetically highly unfavorable to pull two strands apart and use one as a template therefore RNA-dependent RNA polymerase is needed.  Retroviruses do not go the RNA route, instead, they encode reverse transcriptase which changes their RNA into DNA and DNA integrates into host genome. Retroviruses survive much longer in host cells than viruses which use RNA.  In capacity to affect and amount of progeny it can produce retrovirus succeeds other viruses.  Viruses can never have DNA and RNA together as a genome, however hepadnaviruses have double-stranded DNA and partially single-stranded DNA. Reverse transcriptase makes partially single-stranded virus. How do we visualize, detect and titrate viruses?  The simplest tool to understand viruses is by using electron microscopy, x-ray diffraction of crystallized virions.  Plaque assays were first used to detect bacteria but not used to detect viruses as well. o Monolayer is a single layer in a petri dish. o The virus infects the cell and makes new progeny. o Agar is like jello and the progeny virions cannot move anywhere and stay around where they are produced. o Where virions are produced, the cells will die, where the viruses kill cells which most do.  Dilute suspension so the number of plaques is manageable to count. Virus replication: Overview  Estimate the number of cells you have in your dish that you are going to infect and you make sure that you are going to give each cell at least 10-100 virions per cell in that dish. Each cell on that cell at least gets 10 virions. This way you make sure almost all the cells in your dish are going to be infected.  Polyoma means tumours, so mouse polyomavirus creates tumours in a mouse.  Add infectious virus stock to cells, there is a dip where infectious virus cells are lost, as if there is none released. This is the period in which virus replication is happening within the cell. At 18 hours you start getting release and start seeing increase in virus particle constantly and at 40 hours they plateau because pretty much all the cells are dead.  Viral mRNA there is a blip of mRNA, you make it quickly. Viral mRNA corresponds to early viral genes, the red line. T antigen is an early viral protein synthesized by early blip of RNA make early during viral infection. After blip, a whole lot of mRNA produced again, this is synthesis of mRNA for late viral proteins which are capsids. Viral capsid proteins are late viral proteins.  You can make a lot of viral cap but makes no sense in there is no genome to infect so viruses have to replicate DNA and make viral capsid proteins to infect genome.  Uncoat means releasing genome. Use extra replication genome for gene expression. Structural proteins and genomes form together to form new virions through lysis or some other process. Virus replication: receptor binding  Not all viruses infect all cell types and most have specific cell types that they infect.  Tropism means attracted to, going towards, going to attack. Broad tropism means it can go towards many different things.  Example of specific cells is neurons for narrow tropism.  CD4 would be the receptor here. The virus is binding CD4 first.  Co-receptors are CCR5 and CXCR4. Virus replication: entry into the host cell  Most viruses that infect humans do not have drilling mechanism so they fuse with plasma membrane if enveloped or if non-enveloped (and some envelope viruses do this) can be taken into endosome through receptor mediated means. Virus replication: early viral gene expression  One function and one function only of viral genes is to aid in replication of the viral gene.  S phase is the DNA synthesis phase of the cell cycle. Virus replication: genome replication  Many viruses have strategies there they do not allow the cell to make RNA and takes over the process and synthesize viral RNA only. Virus replication: late gene expression & virion assembly  Scaffolding proteins are unique because they are used to just help build the new viral capsid but once the viral capsid is made, they are useless then fall apart. Scaffolding proteins are not apart of mature virion. Virus replication: budding  Envelope glycoproteins have to be on the membrane surface if you want to take plasma membrane as you go.  Second diagram involves middle man, the matrix protein. The matrix protein interacts with RNP and matrix protein interacts with envelope proteins. Then same process as above diagram with budding off.  Third diagram nothing is preassembled and everybody makes their way to plasma membrane. HIV does this.  Direct interaction is must simpler to bud out but with last process things are slowed down. Virus replication: virion release  Some viruses prefer to bud into ER and Golgi membrane rather than plasma membrane and virus is released by exocytosis or when the cell is lysed. For virus replication: review slide, groups should like at if you understand every step for the particular virus you are studying. Antivirals and Vaccines Class IB Antiviral Drugs  It’s a lot difficult to create drugs against viruses because viruses use machinery that we use as well which if we target this machinery will produce nasty side effects. How are antiviral drugs obtained?  Serendipity is a backward approach, discovered by accident.  Other compounds were based on the structure of acyclovir.  Rational approach o Learn a lot about the virus sample. o This drug target has to be crucial to the virus but different from cellular proteins so there are no awful side effects. o The chopping up of HIV is done by anti-HIV protease inhibitor. The drugs attacks this particular step. Antiviral drugs act at different stages of viral infection  In really good shape to block virus at attachment because virus will not even infect cell.  Steps 5-8 usually involve a number of enzymes and our pharmaceutical companies are good at stopping enzyme activity. Antiviral drugs: virus attachment & entry  Normally hydrophobic lipid molecule pocket and virus capsid when attaches to cell surface receptor it displaces the lipid molecule and there is a change in shape in virus molecule and this allows virus to enter cell (the change in shape due to boot of lipid molecule).  Pleconaril causes a conformation change already and it can no longer interact with receptor because it has changed shape already. Antiviral dru
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