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MED2042 WEEK 3 - Virology


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What makes viruses so amazing?
- They can do so much with so little and they can do it elegantly

One of the world's deadliest pathogens:
e.g. Hepatitis B virus (HBV)
- HBV genome contains only four genes
- Over a million people die each year from HBV-associated liver disease
What is a virus?
Parasites of cells
Viruses are supramolecular complexes that can replicate themselves in appropriate cells. They consits of nucelic acid surrounded by a protective shell, or capsid, made up of protein molecules and, in some cases, a membranous envelope.
Describe the two states viruses exist in.
Extracellular state
- virus particle (virion), does not carry out biosynthetic functions. This is the structure by which the virus genome is carried from the cell in which it has been produced to a target cell where the viral nucleic acid can be introduced.

Intracellular state:
- intracellular parasite, virus replication occurs, production of new viral components
What are the properties of a virus?
- acellular organisation
- the presence of either DNA or RNA, but not both, in almost all virions
- Intracellular parasites, inability to reproduce independent of cells
- Cannot make energy or proteins independently of a host cell, viruses lack the genetic information which encodes apparatus necessary for the generation of metabolic energy or for protein synthesis (ribosomes)
- Virus particles are produced from the assembly of pre-formed componenets
- Virus particles themselves do not grow or undergo division
Give examples of how historical classification of viruses was disease related:
Respiratory viruses - influenza, rhinovirus, adenovirus

Enteric viruses - polio, rotaviruses
viruses which replicate in the gut, and cause gastric infections

Arboviruses - alphaviruses, glaviviruses, bunyaviruses transmitted by arthropod vectors

Sexually transmitted viruses - HIV, herpes simplex, papilloma viruses

Hepatitis viruses - viruses causing liver disease
What is the modern virus taxonomy?
- advanced a classical Linnaean system
(phylum, class, order, family, genus, species)

- viruses classified by shared properties rather than the properties of cells/organisms they infect
> nature of the nucleic acid in the virion (DNA/RNA; ss, ds; circular, linear; segmented or single molecule)
symmetry of the capsid
presence or absence of an envelope
dimensions of the virion and capsid

- this basic scheme does not ask what type of cell the virus infects
- no consideration of the disease caused by a virus; related viruses can cause very different diseases
What is a virion?
A virus particle
- a complete physical entity that occurs extrcellularly and can infect new host cells.

A virion is composed of:
- the virus genome (nucleic acid) - in almost all cases DNA or RNA, but not both
- protein capsid (coat) - helical, icosahedral or complex structure
- may have an envelope
- virions range in size from about 10nm to approx. 400nm.
What are the functions of the virion capsid protein?
Protection of the genome
- assembly of a stable, protective protein shell
- recognition and packaging of the nucelic acid genome
- interaction with host cell membrane to form enbelope (possibly)

Delivery of the genome
- specific binding to host cell receptors
- fusion with host cell membrane
- changes that induce uncoating of the gneome
- transport of the genome to the site of replication

Other interactions with the host cell
- transport of viral components to intracellular sites of assembly
Why are capsids constructed from protein subunits?
- due to the limited coding capacity of viral genomes, it is most economical to construct capsids from subunits (genetic economy)
- protein molecules are arranged to provide maximal contact
- repititions of such interactions among a limited number of proteins results in a regular structure, symmetry
List some viruses with a helical symmetry virion architecture.
Tobacco Mosaic virus
Sendai virus
Vesicular stomatitis virus
What is icosahedral symmetry?
- A solid shape consisting of 20 triangular faces arranged around the surface of a sphere
- 12 vertices (vertex: where teh 5 faces meet)
- rotational 2-3-5 symmetry
Describe the structure of virus particles.
Icosahedral or helical (nucleo)capsid surrounded by an envelope

- envelope is host-derived lipid from cell nuclear or plasma membrane
- envelope contains virus-encoded proteins or glycoproteins, project as spikes or peplomers
- envelope may be flexible, unusual shapes
What are complex viruses?
Contain no structural elements that conform simply to helical or icosahedral symmetry.
What are poxviruses?
Smooth rectangles encased within a membrane and protein layer.
State the formula to make up a basic virion.
DNA or RNA + structural proteins +/- enzymes and nucleic acid-binding proteins = nucleocapsid = naked capsid virus

Nucleocapsid + glycoproteins and membrane = enveloped virus
Describe the flow of information.
Gene --transcription--> RNA (messenger RNA)--translation--> protein (sequence of amino acids) --> functioning of proteins within living cells influences an organism's traits
What are the types of nucleic acids in viral genomes?
DNA viruses
- ss DNA
- ds DNA

- ss RNA
- ds RNA

RNA<->DNA viruses
- ss RNA (retroviruses)
- ds DNA (hepadnaviruses)
What are the features of viral genomes?
- linear molecule ( has 3'- and 5'- ends)
- circular molecule (is closed)
- have unusual ends (terminal redundancy, inverted terminal repeats, cohesive termini)
- be modified
- be segmented multipartite genomes
What are the 7 steps of virus replication?
1. Attachment
2. Penetration
3. Uncoating
4. Genome replication and gene expression
5. Assembly
6. Maturation
7. Release
What determines viral host range?
- Attachment of the virus to the host cell
> animal and bacterial viruses - specific receptors on cell are needed for virus attachment
- Presence of an appropriate vector
> plant viruses

Expression of the viral genome within the cell - certain host factors may be needed for virus replication

- Presence of cell surface receptors determines whether a cell is susceptible to a virus
- Only permissive cells allow virus replication

For successful infection cells must be susceptible and permissive --> determines tropism
What are the possible effects of animal viruses on cells?
1. Virus is absorbed into cell
2. virus penetrates to transform cell into tumour cell.
3. Cell is multiplicated.

A number of things can occur
- Tumour cell division causes the tranformation of normal cells to tumour cells
- death of cell and release of virus - lytic infection
- slow release of virus without cell death -
persistent infection
- virus present but not causing harm to cell; later emerges in lytic infection - latent infection
How is the cell cycle regulated?
positively and negatively regulated by different sets of gene produces

Cancer arises:
dominant gain-of function mutations in proto-oncogenes
and recessive loss-of-function mutations in tumour suppressor genes.
How does cancer arise?
Dominant gain-of-function mutations in proto-oncogenes and recessive loss-of-function mutations in tumor suppressor genes.
What protein regulates the G1 to S phase transition in mammals?
Retinoblastoma tumor suppressor protein, pRb.

G1-phase: heterodimeric transciption factor E2F-DP1 blocked pRb

Passage through restriction point.
What was the evidence for RNA-directed DNA polymerase activity?
Discovery in 1970
Extension of the central dogma


DNA --> RNA (transcription)

RNA to RNA (RNA replication)

RNA to Protein (translation)

RNA to DNA (reverse transcription)

1975: Nobel prize in Physiology or Medicine awarded to Howard Temin and David Baltimore
Describe the genome of a virus.
- dimer of linear, positive sense, ssRNA
- each monomer 7-11kb in size
- monomers held together by hydrogen bonds
- RNA polyadenylated, cap
- each monomer is associated with a specific RNA

Purified virion RNA is not infectious
How does HIV cause AIDS (acquired immune deficiency syndrome)?
- HIV infects macrophages and helper T-cells (CD4-positive cells)
- Initial, acute phase: conc. of CD4 T-helper cells declines, conc. of virons increases, then, immune system mobilises against infection, virus conc. decreases CD4 T-cell count recovers
- Chronic phase: ongoing infection, conc. of virions slowly resumes its ascent, CD4 T-cell count resumes its fall
- Below 200 CD4 T-cells/microliter: chronic phase ends, immune system can no longer function, patient develops AIDS

Transmission: person-to-person, bodily fluid containing the virus (blood, semen) carries the virus from an infected person directly onto a mucous membrane or into the blood stream of an uninfected person.
What is the relationship between T-cell counts and viral load?
As viral load increases, T-cell counts decrease.
What is the typical time course of HIV infection and progression to disease?
Primary infection
Acute HIV infection
Anti-HIV immune responses
Clinical Latency
Onset of symptoms
Opportunistic infections
What is a kind of cancer that occurs commonly in a immuno-compromised host?
Kaposi's sarcoma.

A disseminated tumour caused by human herpse virus type 8 is an immuno-compromised host.

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