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Lecture notes

Virus

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Virus

      •         “FILTERABLE VIRUS”

         range in size from 20 nm (10-9 meters) to 250 nm.

         some of the smallest bacteria - the chlamydia and mycoplasma almost as small as largest viruses, that they too can pass through filters that retard 99% of the other bacteria.

         early 1900 diseases like foot-mouth-disease in cattle, some cancers (in animals) and yellow fever in humans caused by filterable viruses.

         "VIRUSES" became permanently associated with this life form.

         discovered in 1915 & 1917.

         Viruses, however were not "seen" until the electron microscope was developed in the late 1930s.

         in 1935 - viruses could be CRYSTALLIZED like inorganic salts (table salt) and protein molecules.

         REPLICATE their genetic material, like all other life forms,

         composed of nucleic acid polymers.

         OBLIGATE INTRACELLULAR PARASITES

         UNABLE to grow and reproduce OUTSIDE OF A LIVING CELL.

         survival absolutely dependent upon continued survival of hosts

         intracellular nature of viruses presents a challenge for investigator who must not only grow virus but also be able to cultivate virus' host cell.

         With plant and bacterial viruses possible to extract sufficient virus from infected host to do analysis.

         viruses were mainly COMPOSED OF PROTEIN AND NUCLEIC ACID.

         in 1931 use of fertilized hen's eggs to culture ( "petri dish”) some viruses.

         first use of artificially cultivated viruses for vaccine production.

         many viruses still grown on eggs - relatively inexpensive and techniques are well established

 

"Are you allergic to eggs?"

         before receiving a viral immunization; means that the virus were grown on eggs and that egg proteins (to which many people are allergic) are present in the vaccine.

         discovery of electron microscope possible to study morphology of viruses.

         it was quickly realized that the size and shape of an individual virus is a constant and distinguishing characteristic.

         therefore a virus's size and shape is always part of its description.

         Viruses may consist of circles, ovals, long thick or thin rods, flexible or stiff rods and ones with distinctive heads and tail components.

         smallest viruses are around 20 nm in diameter and largest around 250 nm.

 

VIRUS COMPOSITION

 

         unique from all other life forms in that they can contain ONLY ONE FORM OF NUCLEIC ACID.

         Either use RNA as their genetic material and other use DNA, but NEVER both.

         nucleic acid polymer may either exist as DOUBLE STRANDED (DS) DNA or RNA or as SINGLE STRANDED (SS) DNA or RNA.

         Each of these characteristics is a constant for a particular virus and is part of it description.

         nucleic acid polymer may contain as few as 4 to 7 genes for very small viruses to 150 to 200 genes for very large viruses, some viruses nucleic acid exists in more than one molecule.

         Some contain a few enzymes,some contain none

         but no viruses contain the large numbers of enzymes found even in smallest bacteria.

         A NAKED virus - protein subunits that make up protective covering around viral genome (DNA), subunits called CAPSOMERES, entire protein coat is called CAPSID.

         An ENVELOPED virus - have a lipid-based membrane surrounding protein capsid, envelope partly composed of cell membrane within which the virus replicated, contains proteins and carbohydrates. Proteins- mixture of  host cell and virus.

 

All viruses are covered with a PROTEIN COAT.

         protein coat mainly composed of a FEW TYPES of proteins of which there are many copies per virus;

         identical protein subunits called CAPSOMERES, made so that they spontaneously come together (ASSEMBLE) in a PREDETERMINED way - produce virus coat called CAPSID.

         All virus contain important proteins type - ATTACHMENT PROTEIN or docking protein(ATTACH TO ITS TARGET CELL before entering host cell).

         attachment protein found on outer surface of virus so easy access with RECEPTOR SITES on target host cells.

         attachment proteins often called SPIKES, they can extend away from cell so as to better contact with  host receptor

         in addition, virus may contain small quantities of carbohydrate (glycoprotein).

         all viruses - LIMITED HOST RANGE and even within a host they attach to and invade only those cells with the APPROPRIATE RECEPTOR SITES.

         specificity is result of same BASIC PRINCIPLE that controls all the other specific mechanisms of life: LIGAND/RECEPTOR BINDING SPECIFICITY.

         smallpox and AIDS viruses only attack man (recently 1995 - first reports of a chimpanzee being infected with HIV reported).

         bacteriophage lambda only attacks cells which contain receptor for binding sugar maltose.

         influenza virus can live in ducks, chickens, wild birds, pigs and humans.

 

Basic principle of viral infection of a given cell:

         if a cell's OUTER SURFACE contains RECEPTOR to which a virus's ATTACHMENT PROTEIN can BIND, virus will be able to invade and grow in that cell

         only applies within RELATED SPECIES or to different types of cells within a host.

         For example, lambda phage will only naturally invade a few species of Gram negative bacteria,

         but if put a plasmid in a G- cell that contains the gene for the lambda receptor, then lambda can bind to and inject its DNA into cell.

         Another example is COMMON COLD VIRUSES.

         viruses are specific for the human UPPER RESPIRATORY TRACK - they contain appropriate AP for binding to receptors on cell membrane of specialized cells in upper respiratory tract.

         Other viruses that cause intestinal diseases only bind to certain receptors of cells in the intestine;

         others bind only to liver cell-receptors and cause hepatitis;

         herpes only bind to receptors on and live in nerve cells.

         Adsorption or DOCKING with the host receptor protein.

         Entry or PENETRATION of the viral nucleic acid into the host cytoplasm.

         BIOSYNTHESIS of the viral components.

         Assembly (MATURATION) of the viral components into complete viral units.

         RELEASE of the completed virus from the host cell.

         Some bacteriophage among larger, more complex viruses.

         phage = head, a tail, a tail plate and tail fibers

         absence of host, long tail fibers WOUND AROUND TAIL, when presence of a suitable host sensed by phage tail fibers UNWIND and extend out from tail plate, increasing area of potential contact with host

         tip of tail fiber contains DOCKING PROTEIN. When one or more of these adsorption proteins contacts a RECEPTOR PROTEIN on host, binds tightly to it, bringing remaining tail fibers quickly into contact with other receptor proteins on host, firmly ATTACHING VIRUS TAIL to host outer wall.

         attachment sets in motion a series of events leading to phage lysozyme lysing hole in cell wall.

         tail fibers contract forcing tail through into cytoplasm.

         DNA from the head is injected host cytoplasm.

         in host's cytoplasm viral DNA take over control.

         produces a special nuclease fragmentation of host's DNA .

         viral DNA produces enzymes and proteins which use host  transcription and translation mechanism to make new virus.

         enzymes MANUFACTURE new phage components in large quantities in cytoplasm; proteins formed assist in maturation process.

         Many phage components SELF ASSEMBLING in made so as to SPONTANEOUSLY assemble into certain PREDETERMINED forms or shapes, - head, tail, tail fibers etc.

         MATURE PHAGE completely assembled ready to begin another life cycle, cell is lysed or ruptured

         mature phage released into environment!

 

TREATMENT/PREVENTION OF VIRAL DISEASES

 

         Major viral disease treatment factors:
1. No viral disease ever been CURED by medical treatment.
2. Viruses not susceptible to ANTIBIOTICS.  

 

         obligate intracellular parasitic nature of viruses difficult to treat

         viral reproduction occurs only inside living cells and mostly uses host cell’s own metabolic machinery to generate new virions,

         difficult task to find /develop drugs both:

            (a) able to penetrate cell’s cytoplasmic membrane

            (b) to selectively damage ONLY viral components.

         Example- drugs that disrupt a virus’ protein or nucleic acid synthesis as well as the host’s system an unacceptable option.

         How then can viral infections be dealt with?

         classical, still most effective, weapon against viruses, immunization.

         Vaccination- arousing a host’s evolved immunological defense against foreign antigens (e.g. specific viruses), prevents infection.

         Vaccination eliminated smallpox a human disease attempting to eliminate polio and measles.

         "extermination strategy" works on viruses limited to Homo sapiens.

         Many viruses survive in non-hominid reservoirs (e.g. influenza &, hantavirus).

         In these cases strategy depends on reservoir(s), , mechanism(s) of dissemination to humans. The most common strategies used in this continuous battle are:

1.      Immunization of hosts with dead or attenuated virus (e.g. flu, polio) or with genetically engineered (G.E.) antigens.

2.      Immunization of hosts using cloned viral DNA shot directly into host cells. Transcription and translation of the viral DNA produces enough viral antigen to immunize the host.

3.      Immunization of hosts using foods containing cloned viral genes that produce viral antigen(s). Hosts ingesting the food/antigen become immune to the virus.

4.      Immunization of humans and alternate hosts (e.g. pets and vets against rabies).

5.      Minimize contact between humans and the natural reservoir(s) (e.g. Hantavirus & mice).

6.      Minimize vector/human contact (e.g. mosquito/yellow fever).

 

         knowledge of viral genetics grown with developing molecular biological strategies for dealing with viruses.

         none can be said to cure an established viral infection, but, by minimizing virus load in infected individual,

         prevent or decrease spread of virus to new hosts (e.g. HIV from mother - fetus) and its damage to

          infected host.

 

Use of analogues that inhibit crucial viral enzymes.

 

  • AZT and acyclovir specifically inhibit replication of genomes of HIV and Herpes viruses respectively.
  • Protease inhibitors inhibit HIV proteases that are required to form a functional virion.
  • Ribavirin blocks genome formation of several viruses.

 

Use of agents that block infection

 

  • Amantadine blocks influenza penetration and uncoating.
  • Monoclonal antibodies bind virus particles in blood which inactivating & marking for destruction by immune cells.
  • G.E. soluble receptors bind virions in blood/serum preventing reaching the cell-bound receptors.
  • All viruses require specific receptors, any virus can be treated this way as long as receptor is known, cloned and produced in large quantities.

 

Use of agents that stimulate or enhance efficacy of host’s immune system

 

  • Interferons (IL-2) kills viruses and activates T-killer cells.
  • Cytokines stimulate killer T-cell production.
  • Cytokines stimulate antibody production.

 

      Physicians cautiously talk of a "CURE" for HIV through use of combinations of above treatments.

      idea - if combined attack can lower virion concentration sufficiently body’s natural immunity can "clean up" remaining virus render host virus free.

      Predictions of outcome not totally unreasonable to consider as in 1997.

      Some neurological diseases are caused by protein infectious particles (PRIONS). These include several animal and at least 3 human diseases. One of these diseases, KURU, infects its victims when they eat the brain tissue of their enemies (a questionable activity at best). The best studied of these diseases is scrapies in sheep. The disease entity seems to be composed completely of PROTEIN and to entirely lack any nucleic acid. This poses a major problem given the significant role of DNA and RNA in life. Three theories are currently being considered to explain prions:

1.      That prions contain, as yet undetected nucleic acid. Extensive purification and testing using the most sensitive methods available have failed to demonstrate any nucleic acid in purified, infectious prions.

2.      that an unknown bacterium that is hard to cultivate and that passes through filters is responsible. Again, there is no proof for such an organism.

3.      That prions represent a type of protein that is able to convert a "normal" protein into a "prion protein". This theory is currently the most popular and there is some evidence accumulating to suggest that it is valid. This theory says that when the prion protein gets into the brain of a victim it binds to a normal or pre-prion protein and somehow converts it into a prion; the new-prion then proceeds to convert other natural proteins. As the number of prions increase destruction of the brain occurs, eventually killing the victim.

 

VIROIDS

 

         Plants fall victim to agents composed of NAKED RNA that are only 300 to 400 nucleotides long, called VIROIDS. The evidence is conclusive that viroids cause plant diseases, but the mechanism of pathogenicity is not known. So far NO HUMAN viroids have been discovered, but it is considered a real possibility that they exist.

 

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