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Flashcards in Viruses Week 6 Deck (106):
1

What is a virus

Group of aceullalar organisms of incredible diversity , submicroscopic , obligate intracellular parasites

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Replication

Are produced from the assembly of pre-formed components, while other biological agents grow from an increase in the sume of their components and reproduce by division. Virions do not grow or undergo division

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Genetic Information

Viruses lack genetic information that encodes the tools neccesary for generation of metabolic energy or for Protein Synthesis

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history of viruses

Ancient Egypt - Poliomyelitis( was the first human disease recognised as a virus)
Pharoah died of smallpox
Small pox was endemic in China

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Variolation development of Small Pox

Inhalation of dried crusts or inoculation of pus from lesions, practice effectivlty prevented disease but could be risky

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Variolation was replaced by vaccination

inoculation by related cowpox virus.
Proved a far safer alternative

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Edward Jenner

used cowpox infected material to successfully vaccinate others

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louis Pasterur

Rabies was caused by a virus. developed a vaccine using an attenuated virus preparation

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Dimitri iwanowski

Diseased tobacco plants could transmit disease

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Martinus Beijernick

Results on tobacco moseaic virus TMV developed modern idea of virus

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1909

Was accepted that viruses could affect human

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Yellow Fever

Spanish American war spread , spread by mosquitos in the 1900 enabled a development of an attenuated disease vaccin in 1937

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Physical Methods of determining Structure

Filtration through membranes of various pore sizes
Sedimentation properties in ultracentrifuges
Spectroscopy
UV light - nucleic acid
Visible light - light scattering properties
X ray diffraction by crystals

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Chemical Methods of Structure of Viruses

Resistance to changes in pH, protein denaturing, like Urea, phenol, detergents

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Electron Microscopy

TMV first published ,
Transmission Electron Microscope and Scanning electron microscope

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Molecular Biology

Virus genome, first completed genome sequence bacteriophage in 1977

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Functions of Virus Particle

Protect genetic material from environment, recognition and interaction with host cell,
delivery of genome to host cell

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Capside

Outer shell of the virus particle , encases the virus genome inside
Protein coat of virus particle

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Physical Constraints

Large nucleic acid molecule must be held in a small capsid

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Envelope

Outer layer lipoprotein bilayer membrane possessed by many viruses

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Genome

Nucleic acid comprising the entire genetic information of an organsism

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Helix

A culindrical solid form by stakcing repeated subunits

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Isosahedron

Solid shape consisting of 20 triangular faces arranged in a sphere

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Nucleocapsid

Ordered complex of protein plus nueclic acid genome of a virus

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Virion

Morphologically complete infectious virus particle

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Helical Capsid

Multiple identical protein subunits arranged in rotational symmetry around a circumference - forming a disk
multiple disks stacked on each other . Genome is coated by the protein in hollow center

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Helical Symmetry

Commonly seen in plant viruses
Many animals have this, but in addition have an outer lipid envelope e.g. influenza virus, mumps, measles, rabies

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Isosahedral Capsid

Arranged protein subunits in the form of a hollow quasispherical structure enclosing the genome within.
Simplest can be built with 3 identical subunits to form each triangular face.
E.g. Picornavirus, Polio, foot and mouth , rhinoviruses

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Virus Envelope

Exiting the host cell without causing distruption is achieved by budding. An evelope is dereived from host cell

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Naked Virus

Do not have a envelope , capside proteins are exposed to external environment
Escape from infected cells at end of replication cycle and causing cell to die

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Disadvantage with Naked Virus

Resulting in premature death of host cell, this prevents an posibility for persistant or latent infections

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Origin of Virus Envelope

Some viruses can derive envelope from host cell, based on helical or isohedral strucutre.
Others may used Golgi or nuclear membrane

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Enveloped Virus formed by budding of host cell membrane

envelope is modified with virus derived proteins

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Virus derived envelope

Matrix proteins
Gylcoproteins
Transmembrane proteins

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Matrix proteins

internal virion proteins that link the internal nucleocapside assembly to the envelope

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Glycoproteins

Anchored to envelope. major antigens and provide contact with external environment

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Transmembrane Proteins

form channels through the envelope allowing virus to control permeability of membrane

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More complex Structures

E.g. poxvirus , containing 100 virus encoded proteins arragned in a variety of internal and external strucutres

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How do viruses successfully assemble

large nucelic acid molecule (-ve charge) must be packaged into a small capsid
Negative charge encounters postivilty charged moleucles like ions and nucelic acid binding proteins
DS DNA genomes may use virus or host derived histone like molecules
Contains specific nucleotide sequence known as packaging signal

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Virus Genomes

RNA or DNA
RNA - single or double stranded
DNA - single or double stranded or particlay DS
SS virus may either be Positive sense (same polarity or nucleotide sequence as mRNA) or negative sense, or ambisense (mixture of the two)
- may have linear, circular, or segmented

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Virus genome size

2500 nuc to 1.2 million bas pairs of DS

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Culture of Viruses

Viruses replicate only in a living host therefore appropriate host is needed

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Quantification of Viruses

determine the number of virions in a suspension, directly counted using a electron microscope
indirectly by measuring the effects on the host (i.e. plaque assay)

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Virus Infectious Unit

Smallest unit that causes a detectable effect when added to a susceptible host

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Virus Plaque assay

Quatification of bacterial virus using agar overlay technique , dilution of a suspension with virus material is added mixed with melted agar and sensitive host bacteria , mixture poured onto agar,
host cells grow, viral particples may cause lysis and spread
Virus replication results in plaques

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Virus Replication

Key to fighting virus infection.
Bacteriophage simple virus has been used as a model
RNA viruses do not need to enter nucleus
DNA viruses mainly replicate in nucelus , some do have ability in cytoplasm

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Replication is 3 phases

Initation of infection
Replication and expression of virus genome
Release of mature virions from infected cell

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Virus Attachment

Specific Binding of a virus attachment protein to a cellular receptor molecule
Receptor helps determine virus tropism - cell type it normally infects

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Virus Penetration

Happens after attachment very quickly Requires energy

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Translocation Penetration

Entire virus translocated across the cytoplasmic membrane of the cell

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Endocytosis Penetration

Most common

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Fusion Penetration

Fusion of envelopes (only for enveloped viruses only)

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Un coating

Following penetration, virus capsid is completely removed or partially and genome is exposed - poorly understood

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Genome Replication and Gene Expression

Once inside cell
Must make virus proteins need mRNA that can interact with host cell ribosomes to direct protein synthesis
Needs to replicate its genome

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Viruses can be divided into 7 groups

Replication strategy

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Class I

DS DNA - Pox, herpes
mRNA production and genome replication similar to host cell genome. make sure that mRNA virus is used in preference to hosts,
Host factors - replication in nucleus
Virus factors - replication in cytoplasm

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Class II

SS DNA - chicken anemia
A second DNA strand must be made, so ds intermediate is formed.

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Class III

DS RNA - reovirus
Have segmented genomes
Transcribe negative sense RNA , to give positive sense mRNA
Viral protein RNA polyemrase is used MUST BE INTRODUCED

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Clas IV

SS RNA - polio

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Class V

SS RNA minu configuration - influenza

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Class VI

SS RNA genome replicates with DNA - reterovirus

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Class VII

DS DNA genome replicates with RNA intermediate - Hep B

e.g. Hep B

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Assembly

Collection of all components necessary for a mature virion at a particlar site in the cell
During assembly , basic structure of virus particle is formed
Assembly may occur in cytoplasms or nucleus
Control is poorely understood

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Mutations

Spontaneous mutation rates may be as high as 10^-3 to -4 incorporated nucleotide (e.g. HIV) for others the rate is a low as that seen in cellular DNA . High rates of spontaneous mutation can generate antigentic variants that can escape the immune response, my also generate defective particles

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Mutations

Mixtures of molecular variants are known as quasispeices .
mechanism is also important in virus evolution

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Mutations may be naturally occuring or artifically in the lab

Due to
Biochemical Markers - including drug resistance mutation or altered virulence
Deletions - recombination
Plaque morphology - mutants may be large plaque mutants (replicate more rapidly than wild type) or small (slowly replicate)
Revertant - involves reverse mutation

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Virus Infection

Result of all the processes of replication and gene expression , most significant response to a virus infection is the activation of the immune system

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Humoral immune response

Production of antibodies typically results in clearance of the virus and stopping the spread of virus to uninfected cells

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Virus host interactions

Eyes, Mouth, respiratory tract, alimentary tract, anus, urogentical tract, skin abrasion /injury arthropod vectors

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Skin Interaction

Mammalian skin is effective barrier to viruses. Outer layer is mainly dead cells, cannot be effected by virus, very few viruses can infect skin unless injury (animal bites), distruption of the skin ecxema abrasions (herpes )

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Some viruses breach the skin by injection

1. Biting arthropods (arboviruses) virus life cycle alternates between an insect vector and a vertebrate.
2. Rabies and B virus may be transmitted by bite of an infected animal
3. HBV,HCV and HIV - transmitted by blood, blood products or contaminated needles

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Mucosal Membrane

Eye and Genitourinary Tract - most favourable routes for access
Spread through bodily fluids sneezing and coughing or sexual contact

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Gastrointestinal Tract

Viruses infecting the gut via the oral route must survive passage through stomach (low pH and high conc of digestive enzymes).
Nevertheless favourable environment for viruses, intestinal epithelium good replicating site, lymphoids tissue associated, constant intake of food, most spread through faecal oral route, poorly treated water or poor hygene , or saliva

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Respiratory Tract

Most frequent site of infection, as with gut, by constant external contact taken in by respiration. Filtering cells, antibodies.

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Virus Host interactions

Natural environment seen as a considerable barrier to viruses , since they are sensitive to heat, drying, UV. Viruses that infect via fecal oral route must survive in the environment and be able to pass the stomach to infect the SI . Many viruses have therefore evolved to take advantage of a secondary vector for transmission

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Without a secondary vector must rely on host to host transmission

Horizontal Transmission
Vertical Transmission

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Horizontal Transmission

Direct host- host mechanism of the virus . relies on a high rate of infection to maintain the virus in the population

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Vertical Transmission

Transmission of the virus from one generation of the hosts to the next . May occur by infection of the fetus, direct transfer in germ line itself, strategy relies on long term persistence of the virus in the host rather than rapid propagation and dissemination

79

Virus Host interactions

1. Direct cell - cell contact - intiamte contact between cells
2. Blood Stream , viruses may get into blood stram via direct inoculation. travel in plasma or in association with RBC, immune cells, Platelets.
3. Nervous System - contact with neurons at the primary site of infetion or via bloodstream. Also transport within the peripheral nerves to CNS, by axonal transport along neurons

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Poliovirus - dissemination via blood

Virus ingested, gut associated lymphoid tissues, then to regiona lymph nodes , then to blood , to blood brain barrier, and then to spinal cord , gut exits in the poos

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Rabies virus - dissemination via neural route

Virus entry through bite in to Striated muscle, to peripheral nerves, to CNS, peripheral nerves then to salivary glands (acinar)

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Local virus spread

Local - occurs by infection of contiguous cells and can results in lesions

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Viremia

Dissemination of viruses through hosts blood stream. In blood the virus may circulate either free in plasma or may be cell associated
Acute
Some are persistant and are in there for months or years

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Primary Viremia

First enters the blood after local replication

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Secondary Viremia

Occurs after virus enters the blood from widely dispersed sites of replication

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Viral Shedding

Viruses that cause acute infectoin usually shed intensivly over a short time period (1-4 weeks)
Viruses that cause persistent infections HIV, HBV) can shed at lower titer for months to years , eventually be trasnmitted during the course of a long lasting infection

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Environment

Variation in humidity or temp of environment may account for seasonality of certain viral infection

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Acute infections

Infections is rapid, cleared by hosts immune defences , and immunity is acquired (min 2 weeks) may be local (rhinovirus) or disseminated (measles)

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Persistent infections

An infection strategy that allows the virus to maintain itself in the host population for a long time.

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3 categories of Persistent infections

Slow
Chronic
Latent

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Slow infection

Viruses progresses slowly but relentlessly toward death . HIV measles encephalitis

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Chronic Infection

Infection with continuing high levels of virus replication and viremia. May be absent, chronic or late to develop. Do not always lead to death
HBV and HCB are two important ones

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Latent infection

Following acute phase , can establish latency, following the immune response. one or more cell types.DNA only , but gene expression is suppressed. Can be reactivated (hepesviruses)

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Host Cytokines

interferon (IFN) mediate many crucal early host antiviral defenses.
Viruses have several strategies to over come these

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Viruses Strategies to overcome IFN

Encode cytokine receptors as decoys, encode cytokin homologs that act as antagonists , block activites of cytokine induced effectors, produced cytokine binding proteins, direclty inhibit cytokin induced gene expression

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Inhibition of antigen presentation

Down regulation of expression of MHC Class I on infected cells

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Evasion of complement - mediated defense

incorporation of host proteins into envelope to protect host cells from complement attack, secreted proteins that accelerate breakdown of C4

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Evasion of antibodies

Antigenic variation (spontaneous mutation)
inherently poor antigens
replication in immunoprivileged sites (CNS)
establishing latent infection in which virus proteins are not epxressed

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Prevention and therapy of viruses

Prevention - public health measures such as water and waste treatment, good medical practice and vector control
vaccination priming the immune system to combat infections

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Vaccinations ....

Recombinant viruses
Plasmid + Part of vaccine in the gene + Foreign DNA insert into host cell and recombination

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Vaccines

Subunit vaccines , containing only a specific protein or two from pathogenic organism (often virus coat protein)

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Vaccines

Live attenuated viruses , with reduced pathogenicity used to stimulate an immune response. generally effective , may be biochemically or gentically unstable may lose infectivity or revert to virulence unexpectantly

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Inactivated Virueses

Virus exposed to a denaturing agent to lose infectivity while retaining antigenicity

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DNA vaccines

use genome of pathogen itself to immunie individual . using fragments or specific genes encoding proteins are used , used in animals as they dont offer as much protection against humans

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DNA vaccines

If translates and if protein produces is immunogenic , the vaccinated animal will be effectively immunised

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Chemotherapy of virus infections

nucleoside anaylogs
Protease inhibitors
Fusion inhibitors
Influenza antiviral agents