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The Story Behind: Retroviral Research
Quick: 5,000 years.
The damage viruses can do is nothing new: It is safe to assume that since the dawn of time, people have been aware of the results of these unseen particles, if not of what they were and how they worked. Perhaps the earliest written evidence of a viral infection comes from Egypt, where hieroglyphs in what was then called Memphis dating to about 3700BC depicts a temple priest with clinical signs of paralytic poliomyelitis.
A continent away and nearly 3,000 years later, in 1000 BC, the Chinese were facing a smallpox crisis. The disease was endemic in their territory and was taking a terrible toll. In the first written record of a successful response to a viral outbreak, Chinese physicians developed variolation. They observed that the survivors of smallpox outbreaks didn't become re-infected in later outbreaks. This led to variolation: the inhalation of the dried crusts from smallpox lesions and, later, inoculation of the pus from a lesion into a scratch on the forearm of a child. It worked, protecting those inoculated against the horrible disease.
Still, no one truly understood what caused the disease. That would take nearly 3,000 more years and the rise of the branch of biology known as virology.
Virology
Chinese variolation represented the state of the art until the 18th century, and even that was largely lost to the West in the Middle Ages - to the point that Edward Jenner, an English scientist and surgeon from Gloucestershire, was credited in the late 18th century with elaborating the principles of vaccination after he successfully used cowpox particles to protect against smallpox.
The next to make a major breakthrough in the field was Louis Pasteur, the famous French microbiologist and chemist who made incalculably important contributions to the fields of virology and microbiology, becoming a pioneer of germ theory, the man who coined the term "virus" and, in 1885, the first person to successfully administer a vaccine for rabies, a horrible virus-caused disease. Pasteur stopped short, however, of discriminating between bacteria, viruses and other infectious agents.
At around the same time, three scientists working separately in three European countries were studying diseased tobacco plants. All three found evidence that the disease could not be caused by bacteria - something smaller had to be at work - and each went on to isolate the virus now known as tobacco mosaic virus (TMV).
Although none of the three discoverers of virus particles then saw the complete picture - or had the tools to really do so - what they discovered was a complex molecule smaller than a bacterium whose only job in "life" is to reproduce itself. And even that it can only do by inserting itself into a host cell and taking over the cell's machinery, in effect turning it into a giant factory for copies of itself.
Today, we know that viruses are essentially little more than genetic material (DNA or RNA) encased in a protein coat or shield known as a capsid. The DNA or RNA is single-stranded in some, double-stranded in others. Some viruses have tails, others tails with baseplates, others still special spikes, all of them designed to help the virus penetrate its host.
In short, viruses come in various shapes, sizes and danger levels. Some infect only one type of host. Others can cross species barriers. HIV, among the best-known and better-studied viruses in the world, is a complex retrovirus.
Despite a number of successful vaccination developments and a deeper understanding of the structure and behaviour of viruses, it was not until the 1960s that the retrovirus was identified. All viruses reproduce by invading and taking over the cells of their victims, then instructing them to produce as many new viruses as possible. Most use their own DNA. However, retroviruses possess an RNA genome, not DNA, and must reproduce by commanding the genome of their hosts. A few years later, researchers figured out how they do it by isolating reverse transcriptase as the key enzyme that retroviruses use to translate their RNA into DNA before integrating it with the host's genome.
Viruses use nucleotides to make DNA. Nucleoside and nucleotide (phosphorylated nucleosides ready for assembly into DNA) analogues work by mimicking the shape and contours of DNA. The virus interprets the drug as a nucleotide from which it can make DNA, and it incorporates the drug into its DNA strand. Once there, the drug blocks the activity of the reverse transcriptase enzyme.
Having no DNA of their own makes complex retroviruses some of the most dangerous viruses in the world because they don't have the normal DNA protections against genetic mutations and so change at an alarmingly high rate. The mutations allow them to quickly grow resistant to antiviral drugs.
Search for a cure
Knowing what retroviruses were was a step forward - now it was time to figure out how to fight them. This was made possible by targeting the reverse transcriptase enzyme itself. Sure, inoculation has been successful against some, but it has a significant drawback: It must be done before a person is infected with the virus. Once the virus has successfully infected a host, there are only two ways to stop it from spreading further and, with many diseases, killing or permanently debilitating the host. Treatment must either somehow neutralise the virus's genetic material or destroy the virus's ability to invade a healthy cell.
Antiretroviral drugs
Antiretroviral drugs are medications for the treatment of infection by retroviruses. Since the identification of retroviruses, researchers have been attempting to find a way to cure them.
In research pioneered by Belgium's Eric De Clercq and his team at Katholieke Universiteit Leuven, the nucleotide analogue has been recently developed. This nucleotide analogue is similar to the nucleoside analogue in that it inhibits reverse transcriptase, but it does not need to be activated, so it can work against the retrovirus in a much wider variety of infected cells. The nucleotide analogue reverse transcriptase inhibitors (NtRTIs), such as De Clercq's tenofovir (marketed by Gilead Sciences, are also significantly less toxic to patients.
It's slow-going, a lifetime's work, but thanks to the efforts of De Clercq, researchers know far more than ever before about the viruses responsible for human cytomegalovirus (CMV), hepatitis B, ebola hemorrhagic fever and HIV, among others.
Indeed, those suffering from HIV/AIDS have De Clercq and his work on retroviruses to thank for a new class of antiretroviral agents that promise to extend the lives of hundreds of thousands of patients.
Read more about the inventor: Erik De Clercq (Belgium)