Introduction & History of Viruses

The study of Viruses is called virology.

Virus Diversity

• More biological diversity within viruses than in all the rest of the bacterial, plant & animal kingdoms put together
• Results from the success of viruses in parasitizing all known groups of living organisms
• At a molecular level, protein-protein, protein-nucleic acid, & protein-lipid interactions determine the structure of virus particles, the synthesis & expression of virus genomes & the effects of viruses on the host cell

Origin of Viruses

Three theories which seek to explain the origin of viruses:

Regressive evolution - viruses are degenerate life-forms which have lost many functions that other organisms possess & have only retained the genetic information essential to their parasitic way of life.

Cellular origins - viruses are sub-cellular, functional assemblies of macromolecules which have escaped their origins inside cells

Independent entities - viruses evolved on a parallel course to cellular organisms from the self-replicating molecules.

History of Virology

• Ancient peoples were aware of the effects of virus infection
• Carried out research into the causes & prevention of virus diseases
• First written record of a virus infection consists of a heiroglyph from Memphis, the capital of ancient Egypt, drawn in approximately 3700BC, which depicts a temple priest called
• Ruma showing typical clinical signs of paralytic poliomyelitis
• The mummified body of Pharaoh Siptah (1200-1193 BC) shows that his left leg was withered and his foot was rigidly extended like a horse's hoof - classic paralytic poliomyelitis
• The Pharoh Ramses V, who died in 1196BC, is believed to have succumbed to smallpox.
• Smallpox was endemic in China by 1000BC. In response, the practice of variolation was developed. Recognizing that survivors of smallpox outbreaks were protected from subsequent infection, variolation involved inhalation of the dried crusts from smallpox lesions like snuff, or in later modifications, inoculation of the pus from a lesion into a scratch on the forearm of a child. 
• On 14th May 1796, Edward Jenner used cowpox-infected material obtained from the hand of Sarah Nemes, a milkmaid from his home village of Berkley in Gloucestershire to successfully vaccinate 8 year old James Phipps
• On 1st July 1796, Jenner challenged the boy by deliberately inoculating him with material from a real case of smallpox
• He did not become infected
• Robert Koch & Louis Pasteur jointly proposed the 'germ theory' of disease in the 1880s that significate the importance of these organisms
• Koch's postulates
• The agent must be present in every case of the disease
• The agent must be isolated from the host & grown in vitro
• The agent must be isolated from the host & grown in vitro
• The disease must be reproduced when a pure culture of the agent is inoculated into a healthy susceptible host
• The same agent must be recovered once again from the experimentally infected host.
• Pasteur worked extensively on rabies, which he identified as being caused by a 'virus' (from the Latin for 'poison') but he did not discriminate between bacterial & other agents of disease
• On 12th February 1892, Dmitri Iwanowski, a Russian botanist, showed that extracts from diseased tobacco plants could transmit disease to other plants after passage through ceramic filters fine enough to retain the smallest known bacteria. This is generally recognized as the beginning of Virology.
• In 1898, Martinus Beijerinick extended Iwanowski's results on tobacco mosaic virus & was the first to develop the modern idea of the virus, which he referred to as contagium vivum fluidum ('soluble living germ')
• Also in 1898, Freidrich Loeffler & Paul Frosch showed that a similar agent was responsible for foot-and-mouth disease in cattle. Thus these new agents caused disease in animals as well as plants.
• Landsteiner & Popper (1909) showed that poliomyelitis was caused by a 'filterable agent' - the first human disease to be recognized as having a viral cause
• Frederick Twort (1915) & Felix d'Herelle (1917) were the first to recognize viruses which infect bacteria called bacteriophages (eaters of bacteria)
• During building of the Panama Canal, yellow fever disease appeared to be spreading slowly. Through experimental transmission to mice, in 1900 Walter Reed demonstrated that yellow fever was caused by a virus, spread by mosquitoes.
• 1935: Wendell Stanley crystallized the tobacco mosaic virus. Suggested that viruses might be chemicals rather than tiny cells

• This discovery eventually enabled Max Theiler (1937) to propagate the virus in chick embryos & successfully produced an attenuated vaccine - the 17D strain - which is still in use today
• In1930s-1950s, animal systems were developing to identify & propagate many pathogenic viruses. Eukaryotic cells can be grown in vitro ('tissue culture') & viruses can be propagated in these cultures.
• In recent years, an entirely new technology has been employed to study the effects on host organisms of viruses: the creation of transgenic animals & plants by means of the insertion into the DNA of the experimental organism of all or part of the virus genome, resulting in expression in the somatic cells (and sometimes in the cells of the germ line) of virus mRNA & proteins

Nature of Viruses

• Sub-microscopic, obligate intracellular parasites
• Produced from the assembly of pre-formed components
• Virus particles (virions) themselves do not 'grow' or undergo division.
• Viruses lack the genetic information which encodes apparatus necessary for the generation of metabolic energy or for protein synthesis (ribosome)
• Segments of DNA or RNA wrapped in a protein coat
• No metabolism
• Must reproduce within cells
• Vary greatly in appearance and size
• Some have membrane outer surface

Structure of Viruses

• Nucleic acid (genome) is DNA or RNA, but not both; it provides the information for directed cell synthesis of new virus particles
• Nucleic acid is enclosed in a protein coat
• Require a cell for replication (remember viruses replicate not multiply)
• Rely upon cell receptors for entry to the cell
• Size:  in the range of 20 - 300 nm
  (Size of S. aureus:  ~ 1000 nm)
• Genome:  DNA or RNA
• Genome size:  in the range of 3000 - 300,000 bp
• Gene number:  1 to >200

Virion Structure

Virion:  a complete virus particle

Envelope: Lipid and protein membrane

Tegument: Amorphous layer between envelope and capsid    

Capsid: Symmetrical protein layer around genome or core

Core: Genome and associated proteins

Viral Structure-Symmetry

Icosahedral

Constructed of 20 equilateral triangular faces e.g. foot-and mouth disease virus

Helical

Tubular construction with the subunits arranged around the nucleic acid in a coil

E.g. rabies virus

Viral Structure (no symmetry organized)

Complex

Not fully understood e.g. smallpox virus

Filamentous

Pleomorphic e.g. ebolavirus

Chemical Structure of the Genome

• All DNA viruses are double stranded (except circoviruses and parvo viruses)
• All DNA viruses have a single
• Molecule of nucleic acid (not segmented) (most of virus is protein)
• RNA viruses may be a single molecule, double stranded, or segmented and either + or – single strand

Chemical Structure-Proteins

• Structural
• Important for viral stability and attachment
• Non-structural
• Enzymes involved in viral replication
• Antibodies are generally formed against the structural proteins. 

What do virion proteins do?

• Protect nucleic acid
• Attach to receptors on cells
• Penetrate cell membrane
• Replicate nucleic acid (some viruses)
• Begin program for replication (some viruses)

Five basic structural forms of viruses in nature

Naked icosahedral e.g. poliovirus, adenovirus, hepatitis A virus  

Naked helical e.g. tobacco mosaic virus. So far no human viruses with this structure are known

Enveloped icosahedral e.g. herpes virus, yellow fever virus, rubella virus

Enveloped helical e.g. rabies virus, influenza virus, parainfluenza virus, mumps virus, measles virus

Complex e.g. poxvirus 

Viral Shape

• Quite varied
• Helical (Rodlike or threadlike)
• Isometric (Icosahedron)
• Complex

Virus Structure-General Comments

• Function of the outer shell (CAPSID) of a virus particle is to protect the fragile nucleic acid genome from
• Physical damage - Shearing by mechanical forces
• Chemical damage- UV irradiation leading to chemical modification
• Enzymatic damage - Nucleases derived from dead or leaky cells or deliberately secreted by vertebrates as defence against infection
• Protein subunits in a virus capsid are multiply redundant, i.e. present in many copies per particle. Damage to one subunit may render that subunit non-functional, but does not destroy the infectivity of the whole particle.

Viroids

• Small (200-400nt), circular RNA molecules
• Rod-like secondary structure possess no capsid or envelope
• Associated with certain plant diseases
• Obligate intracellular parasites

Virusoids

• Satellite, viroid-like molecules, somewhat larger than viroids, dependent on the presence of virus replication for multiplication (hence 'satellite')

Prions

• Rather ill-defined infectious agents
• Consist of a single type of protein molecule with no nucleic acid component.
• Creutzfeldt-Jakob disease in humans, scrapie in sheep & bovine spongiform encephalopathy (BSE) in cattle

Properties of Viruses

Heat sensitivity

• Relative to time and a function of protein denaturation (enveloped viruses more sensitive)

pH sensitivity

• Extremes are destructive

Lipid solvents

• Enveloped viruses generally more sensitive

Chemicals

• React with amino acids of proteins, but some inactivate DNA or RNA

Radiation and Ultraviolet light
Virus differ from other intracellular obligatory parasites

• Ultramicroscopic
• Unique structure
• Unique replicative cycle (not binary fission)
• Contain either RNA or DNA (not both)