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Slow progress towards effective 
anti-virus drugs

Dr Jim Robinson discusses the recent literature about the search for a “silver bullet” for virus infections.
The amazing success against bacterial infections of penicillin and the subsequent 140-plus antibiotics that have saved millions of lives, led to hopes that a similar “miracle cure” would emerge to do something similar against viruses in animals, birds, fish and mankind. We know that the antibiotic armoury of drugs has not been without disadvantages in the form of allergies, toxic risks, resistance development by some bacteria and misuse in cases where the wrong choice of the particular drug has had serious consequences. On balance, there can be few who would argue the view that antibiotics are one of mankind’s major discoveries and developments.
Virus diseases are pathogenically as destructive and economically dangerous as those caused by bacteria, and to name some that affect pigs, for example, we have to deal with:
•    Foot and mouth disease (FMD, with at least seven variants), African swine fever (ASF), classical swine fever (CSF), porcine respiratory and reproductive syndrome (PRRS), porcine circovirus 2 (PCV2 or fading piglet syndrome), rotavirus, parvovirus, pig pox, and an assortment of porcine enteroviruses, to name enough for the purpose. There are also a number of others  that are threatening to invade from other countries, such as:
•    Aujeszky’s disease (pseudo-rabies), transmissible gastro-enteritis (TGE) and its newly troublesome fellow-corona virus called porcine epidemic diarrhoea (PED), swine influenza (the real one, not the others), paramyxovirus (blue eye) and doubtless others that are so easily transported around the globe.
Differences between bacteria and viruses
To appreciate why, with the knowledge gained from how antibiotics work against bacteria, researchers have not come up with a single substance or group of substances that will revolutionise antiviral pharmacology, we need to understand a number of differences between the two micro-organisms.
Life cycle and multiplication
Bacteria, with some exceptions, live their own life independently of the larger creatures they may attack and make sick in the course of perpetuating their own species. Some protect themselves by means of spores, coatings, multiple hosts and so on, but all use the victim animal as a source of nutrient, not as an essential part of a life-giving multiplication system.
Viruses are different: they can only reproduce by using the systems of a living cell.  Their method of replication involves a series of events:
•    Attachment: the virus particle arrives on the host cell wall and binds itself to a receptor molecule;
•    It then either penetrates the cell and “uncoats” itself, or injects some or all of its nuclear material (DNA or RNA) which takes control of the ribosomes and other enzyme systems in the host cell body and instructs them, by means of messenger RNA, to manufacture its specific virus nucleic acid (NA) multiple times – even thousands of new virus particles may be produced from one infected cell;
•    The components of the new virus are re-assembled into whole viruses which burst out of the now destroyed host cell and then move, or are transported by the host’s lymphatic system or bloodstream, to the next target cells and repeat the process. (This gives real meaning to the current expression used by YouTube addicts when they say the video “went viral”).
Pathogenicity of viruses:
Viruses do harm in a number of ways:
•    They may physically destroy the host cells by multiplying and using the mechanisms of the cell and breaking out through the cell wall; this causes a reaction in the host with fever, disturbed function and physical incapability;
•    Some produce toxins which poison the host, both locally and through the bloodstream;
•    Some produce proteins which supress various elements of the host’s immune system—HIV is the best known of these, but not the only one—which compromises the defence mechanism of the host animal or person against attacks by other disease-causing infections;
•    Some invade the cell and do not destroy it but become dormant while altering the nucleus and consequently the genetics of the cell which may become abnormal, uncontrolled and malignant. It is estimated that 15 to 20% of cancers are caused by viruses.
Problems with treating virus infections
Natural defences
Clearly not all virus infections are fatal, partly because they are relatively slow in their replication or relatively benign in their cell occupation and mainly because the host animal has a functioning and successful immune system. This includes:
•    humoral antibodies carried as proteins in the lymph and bloodstreams which result from exposure of the animal to nonfatal attacks or from vaccination and are fairly specific for particular organisms;
•    white blood cells, macrophages, killer cells and others that are activated by foreign invaders and are less discriminating in their target selection;
•    interferons (IFN), proteins produced naturally in all animals, and in raised quantities when virus infections are detected. IFN has the ability to retard the activities of invading viruses and to alert neighbouring cells and the immune system to their presence.  IFNs are used in human medicine for certain diseases including certain  cancers with apparently some success but are not, as yet, a panacea.
Antibiotics are not effective against viruses, largely because the virus virtually becomes part of the host cell and anything that can kill the virus would kill the host cell as well, and not only the affected cells but the rest of the host animal too.
Chemical remedies
An increasing armoury of chemical and pharmaceutical drugs is nevertheless building up, as a result of intensive research. The so-called “candidate drugs” are required  to meet certain criteria:
•    “target proteins” such as specific enzymes or parts of proteins in the virus need to be identified; these must be essential for the viability of the virus but unlike others which are part of the normal host cell;
•    These targets should be common to more than one species of virus, so that  any effective drug will have the widest possible use;
•    Once identified, these target proteins must be synthesised in the laboratory so that candidate drugs can be tested against them.
In order to do this, the gene that synthesises the target protein in the virus must be inserted into living cells such as bacteria which can be cultured in the lab to produce enough target protein to test the effectiveness of candidate drugs.
•     Many of the target proteins have been identified and are being disabled so that the virus is unable to perform its function at the various stages of its life cycle.
For example:  in some but not all virus attacks—
•    The attachment protein can be mimicked and even have an antibody incorporated so that there is nowhere for the infective process to begin;
•    Entry-blocking drugs (being used successfully for the HIV-type viruses) prevent the injection or invasion of the virus DNA;
•    Uncoating inhibitors are making progress, and so are NA-like proteins that resemble the building blocks of the multiplying viruses but de-activate the enzymes that create the specific virus DNA or RNA;
•    A new approach, creating “anti-sense” molecules which are complementary pieces of virus DNA that insert themselves into the genome during re-synthesis and block the operation of putting together new virus in the parasitised host cell.
None of this is rapid with “Eureka discoveries” along the way, but the science of genomics is making real progress in a logical and rational path to virus remedies:
If not yet a silver bullet, at least a growing arsenal of  bronze ones are making virus disease treatment more feasible and successful every day.
References:
Most of the information summarised here comes from that very useful (and often underrated) fount of knowledge, Wikipedia the free encyclopaedia which, in turn, has a comprehensive bibliography for reference and further reading.

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