Why are viruses such challenging foes?

Analysis: despite the huge advances made in the development of new medicines, our arsenal of effective anti-viral drugs remains limited

By Tim O'Sullivan and JJ Keating, UCC

The current Covid-19 pandemic has brought into sharp focus the threat that viruses pose to humanity. History is replete with examples. During the four years of the First World War, the total number of combatant and civilian deaths is estimated to have reached 20 million. But this shocking death toll is just a fraction of the more than 50 million people who died as a result of the H1N1 virus (known as the Spanish Flu pandemic) during 1918 and 1919.

If we broaden our view to encompass the entire 20th century, the total number of deaths associated with warfare amounted to 108 million. Yet, during that same 100-year time period, approximately 300 million people succumbed to the smallpox virus alone.

Despite the huge advances made in the development of new medicines, our arsenal of effective anti-viral drugs remains limited. This is in sharp contrast to the very large number of broad-spectrum antibiotics which have been developed since the 1940s, specifically designed to target bacterial infections. As we are often reminded, antibiotics are ineffective in treating the viruses that cause the common cold or 'flu.

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Ironically, a major reason why viruses present such a challenge to medicine is their relatively uncomplicated biological architecture, consisting merely of strings of genetic material surrounded by a protein coat. Due to their primitive structures, scientists do not consider viruses to be living entities.

By contrast, bacteria and parasites, which are the other main drivers of infectious disease in humans, are living single cell or multicellular organisms, and are far more complex in their makeup. Their inherent complexity presents researchers with multiple avenues of attack. Many antibiotics, for example, interfere with the walls that surround some bacterial cells. These walls are absent from human cells, and this biological difference enables researchers to design drugs which specifically target bacteria. Penicillin, one of the first antibiotics discovered, works in this manner by impeding the construction of bacterial cell walls.

As viruses are relatively simple structures, they lack the necessary wherewithal required for self-replication. Instead, they highjack the molecular machinery of host cells to generate new copies of the virus particle. This "cell-jacking" not only enables the virus to spread, but ultimately results in the destruction of the infected cell. If scientists set out to disrupt this viral replication process, they must ensure their drug does not also interfere with the normal functioning of the host cell. Failure to avoid this could lead to potentially serious side effects.

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Additionally, viruses typically do not possess a robust error-checking system. This inevitably leads to relatively high levels of mutation of the viral genetic code during their replication which, in turn, helps drive evolution of the virus. Having discovered an initially effective anti-viral agent, researchers can soon find that their drug becomes increasingly ineffective due to mutations of the viral genome over time.

Scientists often make an analogy of drugs interacting with their target as a key fits into a lock. If the shape of the key matches the shape of the lock, then the key can open the lock. Likewise, if the shape of a drug molecule complements its target, a biological response will occur and the disease can be treated. This will often involve "switching off" an enzyme which is implicated in the disease.

However, if the target undergoes a mutation during replication (such as often occurs with viral drug targets), this can result in a small, but significant change which renders the drug useless. Effectively, the lock has been changed and the key no longer fits. This tendency of viruses to mutate not only poses a challenge for designing new anti-viral drugs, but also for the development of long-lasting vaccines.

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One successful treatment strategy against rapidly evolving viruses is the use of ‘combination therapies’. These medicines comprise of two or more drugs, with different mechanisms of action, administered simultaneously to a patient. Combination therapies are designed to interfere with different processes in the same virus. The probability of a virus undergoing a double mutation which circumvents the inhibitory effects of two different drug classes is exceedingly small. This polydrug treatment approach has proven remarkably successful against the human immunodeficiency virus (HIV). Deaths related to Acquired Immunodeficiency Syndrome (AIDS) have fallen by 60% since their peak in 2004, in large part due to anti-viral combination therapies.

Another notable success against viral infections has been in the treatment of hepatitis C virus (HCV). Until relatively recently, Egypt had one of the highest HCV infection rates in the world, reaching a high of over 500,000 new infections annually in the mid-1990s. The rollout of nationwide HCV testing, coupled with the widespread use of anti-viral drugs, has seen this disease rate fall to less than 90,000 infections per year, with further decreases in infection rates expected into the future.

Of course, prevention is better than cure and vaccines are without equal in this regard. For those viruses against which vaccines have been successfully developed, the adoption of mass immunisation has proven hugely successful. In some cases, this approach has resulted in global eradication of a virus, as in the case of smallpox, arguably one of the crowning achievements of the 20th century.

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Many countries, including Ireland, have school campaigns encouraging the vaccination of young people against human papilloma virus (HPV). This virus is associated with the development of cervical cancer in women, and other cancers in both men and women. HPV vaccinations aim to reduce the levels of these cancers in the general population. Other viruses, however, such as HIV, have thus far outwitted our attempts to discover an effective vaccine.

If any benefits can be said to have arisen from the Covid-19 pandemic, then they must surely include advances in vaccine research, most notably in the development of messenger ribonucleic acid (mRNA) vaccines. While our ancient battle with viruses will inevitably continue, our suite of countermeasures and our understanding of viruses has never been greater.

Dr Tim O'Sullivan and Dr JJ Keating are Lecturers in Pharmaceutical Chemistry at the School of Pharmacy and School of Chemistry at UCC

The views expressed here are those of the author and do not represent or reflect the views of RTÉ

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