MED2042 WEEK 3 - Virology
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- What makes viruses so amazing?
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- 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?
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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.
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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?
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- 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:
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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?
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- 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
NB:
- 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?
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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?
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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?
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- 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.
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Tobacco Mosaic virus
Sendai virus
Vesicular stomatitis virus - What is icosahedral symmetry?
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- 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.
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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.
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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.
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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?
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DNA viruses
- ss DNA
- ds DNA
RNA
- ss RNA
- ds RNA
RNA<->DNA viruses
- ss RNA (retroviruses)
- ds DNA (hepadnaviruses) - What are the features of viral genomes?
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- 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?
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1. Attachment
2. Penetration
3. Uncoating
4. Genome replication and gene expression
5. Assembly
6. Maturation
7. Release - What determines viral host range?
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- 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
Tropism
- 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?
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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?
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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?
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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?
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Discovery in 1970
Extension of the central dogma
DNA --> DNA
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.
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- 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)?
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- 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?
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Primary infection
Acute HIV infection
Anti-HIV immune responses
Clinical Latency
Onset of symptoms
Opportunistic infections
Death - What is a kind of cancer that occurs commonly in a immuno-compromised host?
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Kaposi's sarcoma.
A disseminated tumour caused by human herpse virus type 8 is an immuno-compromised host.