VIRUSES  VERSUS  HUMANS:  MOLECULAR  EVOLUTION  AT  WORK

MANILA
, JANUARY 13, 2007
  (STAR) STAR SCIENCE By Mishail Tupas - The common cold, the flu, autoimmune deficiency syndrome (AIDS), hepatitis, meningitis, measles, severe acute respiratory syndrome (SARS), hemorrhagic fever, certain cancers… the list just goes on and on. These debilitating diseases, many of which are fatal, are caused by viruses, the smallest known parasitic microbe. The recent outbreak of SARS, caused by the SARS corona virus (SARS-CoV) originally infecting chickens; the scare in the increase of encephalitis, high fever, and other respiratory syndromes due to the West Nile virus; and anxieties over the flu because of the vaccine shortage, indicate how these tiniest of all microbes affect the quality of human life.

Viruses wreak so much havoc because they can easily sneak past the immune system, resulting in millions of deaths per year globally. Viruses are simply genetic information in the form of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) surrounded by a protein coat. Most of the viruses that cause certain cancers are DNA viruses while those that cause common or chronic respiratory and immune diseases are RNA viruses, and include the human immunodeficiency virus (HIV), SARS-CoV, influenza virus, and the West Nile virus. Retroviruses like HIV are the most deadly of these, because once inside the host cell their RNA is reverse transcribed into DNA, where it subsequently integrates into the host genome and can remain undetected for years.

It is not surprising that new viruses with increasing virulence are discovered every year. Viruses undergo evolutionary changes in their genetic information, creating new viral particles that are unrecognizable to the host immune system. The process is part of what is now called molecular evolution. There are two main mechanisms for molecular evolution: genetic drift and genetic shift. Genetic drift is when genes are gradually changed over time and is the most commonly known form of evolution. Genetic shift is when a large amount of DNA or RNA is changed, which in viruses can be attained through re-assortment, or when two different viruses infect the same cell and their RNA get mixed up.

These molecular changes allow viruses to develop new strains in a short period of time, therefore displaying the fastest rate of molecular evolution. For example, the mutation rate among DNA viruses is around 0.1 per genome (viral genome is about 10,000 nucleotides) per replication, while the mutation rate of influenza and corona viruses, which are RNA viruses, is about 10 times faster. The high mutation rate of RNA viruses compared to DNA viruses is responsible for their enormous adaptive capacity which often results in a new and sometimes more virulent strain.

A good example of rapid molecular evolution is displayed by the influenza viruses, RNA viruses in the family Orthomyxoviridae. Although there are three types of influenza viruses (A, B and C), it is the Influenza A virus that causes the flu pandemics known to infect humans, other mammals and birds. Influenza viruses express surface antigens known as hemagglutinin (H) and neuraminidase (N) proteins which are glycoproteins found on the outside of the viral particle essential for viral reproduction and periodically undergo mutation. The hemagglutinin and neuraminidase proteins are targets for antiviral drugs and are also recognized by antibodies, i.e. they are antigens. The responses of antibodies to these proteins are used to classify the different serotypes of Influenza A viruses, hence the HxNx identification system.

Scientists believe that during the 1918, 1957 and 1968 flu pandemics, a mix of avian or swine and human flu viruses resulted in new H and N proteins, making it difficult for the human host immune cells to muster up a response because they could not recognize the avian or swine component. The 1918 pandemic alone resulted in the loss of 40 million lives around the world. In January 2003, human diseases associated with Influenza A virus subtype H5N1, also known as A(H5N1) or H5N1, re-emerged for the first time since an outbreak resulting in human deaths was reported in 1997. The bird adapted strain of H5N1is called HPAI A(H5N1) for "highly pathogenic avian influenza of type A, subtype H5N1" and is the causative agent of the H5N1 flu commonly known as avian influenza. Avian influenza technically denotes the disease, not the virus. It is the Influenza A virus that causes avian influenza, now recognized because of its global spread through multiple bird species as a significant pandemic threat.

The high mutation rates of the influenza and corona viruses enable them to infect new hosts across species and give them the edge in emergence. So far there are 15 H proteins and nine N proteins that have been discovered, with a total of 135 different combinations of both proteins. This extensive pool allows the viruses to escape immune detection and infect new species, keeping vaccine manufacturers guessing as to the next prevalent strain for the coming year.

The human immune system is able to respond to these viral infections because they have cells that also undergo molecular evolution. In complex organisms such as humans molecular evolution takes place at a rapid pace but is limited to particular immune cells such as B-lymphocytes. These cells are able to produce a large quantity and variety of virus-fighting antibodies through molecular changes in the immunoglobulin genes. In response to infection, these genes undergo rearrangement or recombination at very high frequency in a specific region known as the variable segment. This high frequency mutational event is known as somatic hypermutation, which results in the production of a large variety of antibodies. Thus, the B-lymphocytes are able to make a whole range of antibodies against a large number of infectious agents, thereby ensuring the survival of the organism. Mutation rates during somatic hypermutation can be as high as 0.001 per base synthesized per generation, which are still several orders of magnitude lower than the mutation rates of RNA viruses. One of the risks for an increased mutation rate and hyperactivation of the immune cells is the development of autoimmune diseases, where the host attacks its own cells, resulting in their death.

Molecular evolution in human B-lymphocytes is not fast enough to combat the rapidly mutating viruses. Humans have developed other means to overcome these pathogens through the use of vaccines that stimulate a faster immune response without resulting in immune hyperdrive. Although this is some form of adaptive response from the host, with the high mutation rates among viruses, it seems that availability of the appropriate vaccine may lag behind viral molecular evolution. With viruses replicating in a matter of minutes, they consequently have thousands more mutations than humans would ever have within a generation time of 20 years.

A generally accepted concept in the theory of natural selection and mutation is that organisms with short replication times will more often undergo mutations and pass it on to the next generation. The fact that the flu virus mutates at such an astonishing speed and the recent flu vaccine shortages, Klaus Stöhr, head of flu surveillance at the World Health Organization, declared in November 2004 that "a global influenza pandemic is closer than at any time in a generation." Molecular vaccines would be a way to equalize this situation because these vaccines can be changed more rapidly than traditional ones to counteract new viral strains. This is the future direction in vaccine therapy.

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Mishail "Miko" Tupas is a 9th Grade student at Oakton High School in Fairfax, Virginia. This article was adapted and expanded from his 7th Grade entry to the 2005 DuPont Challenge Science Essay Competition. He is the son of Dr. Luis Tupas and Dr. Jermelina Garibay-Tupas, alumni and former faculty members of the University of the Philippines and currently scientific program directors at the US Department of Agriculture and US National Institutes of Health, respectively. E-mail Miko at mikotupas@cox.net.


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