(7) Virology
WORLD HEALTH ORGANIZATION - Pandemic and Epidemic Diseases
Viruses past, present and future
The study of viruses is less than 100 years old, but viruses themselves are ancient parasites whose history and evolution is closely entwined with our own.
Until the farming revolution began some 10,000 years ago, our ancestors were hunter-gatherers, living in small groups and constantly moving from place to place. The population was sparse, but still persistent viruses like the herpes viruses were able to thrive. They are clearly well adapted to the hunter-gatherer lifestyle, managing to infect almost everyone by biding their time until they could be passed on from one generation to the next. These viruses probably posed little threat, but with the change to the more settled farming lifestyle came the problem of zoonoses. The many ‘new’ viruses that jumped from domestic animals to the early farmers caused severe infections. By killing off the most susceptible in the population, these microbes have influenced our social history.
Smallpox virus in particular has killed untold millions since it transferred from its animal source, an event that probably took place around 5,000 to 10,000 years ago in the early communities of the fertile Eu around 5,000 to 10,000 years ago" ( Hphrates, Tigris, Nile, Ganges, and Indus river valleys where farming thrived. Certainly, ancient Egyptian texts written around 3730 BC refer to a smallpox-like disease, and some Egyptian mummies, including that of King Ramses V dating from 1157 BC, have skin lesions resembling smallpox.
The first documented epidemic was the plague of Athens in 430 BC that occurred during the Peloponnesian War between the Athenians led by Pericles and the Spartans and is thought by most experts to have been caused by smallpox. When Pericles decided to enclose Athens against the advancing Spartan infantry, he was unknowingly providing microbes with an ideal environment to thrive. As the city became severely overcrowded with refugees fleeing the advancing Spartans, the virus took hold, raging for four years and killing thousands, including Pericles himself. This spelled doom for the Athenians, and their defeat heralded the end of the Greek Empire.
As the populations of cities in Europe and Asia grew, so smallpox became a regular visitor, killing up to 30% of those it infected. As testimony to its devastating effects, the Indian tribal goddess Shitala, the Chinese goddess T’ou-Shen Niang-Niang, and the Christian saint Nicaise are all dedicated to smallpox, prayed to by the masses in the hope of preventing, or being cured of, the infection. Although the virus tended to hit the poor in their crowded, airless dwellings, the royalty of Europe were also dealt a blow from time to time. In the 18th century, smallpox caused the demise of the House of Stuart in the UK (1603-1701), with other royal victims of the time including Joseph I of Germany, Hungary, and Bohemia (1678-1711), Louis I of Spain (1707-1724), Louis XV of France (1710-1774), Ulrika Eleonora of Sweden (1688–1741), and Peter II of Russia (1715-1730), all dying within an 80-year period.
Smallpox was unknown in the ‘New World’ until it was introduced, along with many other microbes, by the Spanish conquistadors in the 16th century. With no immunity or genetic resistance to the virus, Native Americans suffered severely. Whole tribes were wiped out, and the population dropped by 90% over the following 120 years. When the Spanish invaders arrived, the Aztecs in Mexico and the Incas in Peru each had a population of 20 to 30 million, with massive armies. Nevertheless, in 1521 Hernando Cortés defeated the Aztecs with around 600 soldiers, and Francisco Pizarro similarly conquered the Incas with just 200 men in 1532. Both men were aided by smallpox, possibly combined with other microbes that concomitantly killed up to half the population leaving the survivors so confused and demoralized that the Spanish invaders had easy victories.
Plant viruses have also had their moments of glory, and one such occurred during the 17th century when ‘tulipmania’ hit Holland. Tulips had recently been imported from Turkey and Dutch plant breeders were busy developing new varieties, including ‘broken tulips’ with white stripes on their flowers called ‘color breaks’. Owning such a plant became a status symbol in Holland, where between 1634 and 1637 a single bulb of the prized ‘Admiral van Enkhuiijsen’ variety could change hands for up to 5,400 guilders, the cost of an Amsterdam town house and 15 times a laborer’s annual wage. But the plants were weak and unreliable; only occasional bulbs produced broken flowers and no one could work out why, or how to encourage the trait. The explanation is that the Dutch grew their bulbs in fields surrounded by fruit trees and virus-carrying aphids from the trees randomly dropped onto the tulips, infecting the plants, meningitis, encephalitis, and er6Psuppressing color formation, and weakening the bulbs. Today, the multitudes of variegated plants on offer at garden centres are also virus-infected and for that reason are generally not as vigorous as their plain-colored counterparts.
Viruses, like other microbes, frequently use insects or other vectors to spread between hosts. The
yellow fever virus uses mosquitoes to jump from one monkey to the next in the rain forests of West Africa. Infected monkeys remain healthy but if a virus-laden mosquito bites a human it causes a potentially deadly disease. This may be a flu-like illness, but in up to 20% of cases it progresses to a haemorrhagic fever with a high mortality. Humans often pick up the virus while felling trees in the jungle, an occupation that brings the infected mosquitoes down from the tree canopy into direct contact with the tree-fellers. Once humans are infected, the virus can be spread from person to person by urban mosquitoes, so causing an epidemic.
Yellow fever first appeared in the New World in the mid-17th century having hitched a ride aboard slave ships. Since the virus does not persist in those who recover from the infection, it must have survived the journey by infecting a series of victims on board, ferried between them by mosquitoes breeding in the ship’s water barrels. Virus-carrying mosquitoes from the ships then moved inland and established an outpost in the Americas where they remain today. Yellow fever caused devastating epidemics in both South and North America, killing thousands before the link with mosquitoes was unraveled in the late 19th century and preventive measures were taken.
Undoubtedly, yellow fever virus, along with smallpox, measles, malaria, and other imported microbes, had a hand in the depopulation of the Caribbean islands, attacking Native Americans, African slaves, and European settlers with equal ferocity. Indeed, Napoleon intended to make Santa Domingo the capital of his New World Empire and port of entry to the French property of Louisiana until yellow fever put a stop to his dreams. His army was unable to quell the slave rebellion led by Toussaint Louverture that began in 1791. Although he sent reinforcements, by 1802 his army had lost more than 40,000 troops, many to yellow fever. They were forced to surrender and quit the island, so ending Napoleon’s hopes of expansion into the New World, and he sold the state of Louisiana to the US for 15 million dollars.
Yellow fever also defeated French attempts to build the Panama Canal in the late 19th century. They struggled for 20 years before giving up. The project was completed by the Americans in 1913 with a total death toll of 28,000 and a cost of 300 million dollars.
Small as they are, viruses still have the power to undermine our social structures today. From its small beginning in the rain forests of Cameroon around 100 years ago, HIV has caused the largest human pandemic in living memory. Over the last 50 years, it has ravaged sub-Saharan Africa, wiping out a generation of young people and depriving the next of family life and an education. The worst-hit countries have lost their valuable work force, plunging millions into poverty and accentuating the world’s rich/poor divide. The HIV front has now moved to South-East Asia and Eastern Europe, where Russia has an estimated 1.5 million infected people. All along, governments’ responses have largely been too little too late, and politicians appear powerless to stop its advance.
The blood and blood products and aid, such as self-help programmes and the appropriate education can provide for their sustainability. The HIV pandemic is history-in-the-making; only time will tell what effect it has had on the world’s social development.
What can we expect from viruses in the future?
We know that viruses are everywhere and that the virosphere is hugely diverse. This reservoir will certainly throw up new human pathogens from time to time; the question is: are we prepared? More specifically, can we predict, control, treat, and prevent new human virus infections? We saw how the genomic revolution impacted on virology, providing new, rapid diagnostic tests, targeted vaccines, and designer antiviral drugs. The outcome of the SARS epidemic in 2001 shows how these tools can be used effectively. As soon as the SARS corona virus was identified, its genome was sequenced and diagnostic tests were prepared, all within a matter of months. The culprit animal source in Chinese wet markets was uncovered and now bats have been identified as the most likely long-term animal reservoir. Should the virus raise its ugly head again, we are ready with antiviral drugs and vaccines. A similar scenario, although on a much wider scale, occurred during the 2009 swine flu pandemic. The virus genome was rapidly sequenced, antiviral were made available for prevention and treatment, and a vaccine was prepared within six months. Even so, both SARS and swine flu had spread far beyond their point of origin before they were identified as a threat, indicating that prediction of an outbreak can be the weak link in the chain.
Although we know that most emerging viruses, including flu and SARS, jump from animals to humans, we are far from predicting when and where the next viral threat will appear. Indeed, in the case of flu, ever since the 1950s when WHO established the Global Influenza Surveillance Network involving over 90 countries, great efforts have been made to spot new flu strains that might cause the next pandemic. But still in 2009, when all attention was focused on the H5N1 bird flu in Asia, the emergence of H1N1 swine flu in Mexico went unnoticed. Clearly, studying and monitoring potentially threatening viruses in their primary animal host, like flu viruses in wild birds and retroviruses in primates, is a sensible way forward. But this would be a time-consuming and expensive occupation that few governments or agencies are prepared to fund. At present, all we can do is keep a sharp lookout for new clinical disease patterns that might indicate an emerging infection and nip it in the bud.
In parallel to hunting for emerging viruses, we can also search for viral causes of ‘orphan’ diseases. One such is chronic fatigue syndrome (CFS; previously called myalgia encephalomyelitis, or ME), which has long been recognized as a rather vague collection of symptoms. Recently, it has been defined as ‘severe physical and mental fatigue without other clinical signs that is not relieved by rest and is of at least six months’ duration’. The syndrome affects around 250,000 people in the UK and has now been recognized by the UK Department of Health as a debilitating, chronic disease. However, the cause of CFS is unknown; some favor a psychological origin while others suspect an infectious agent. Potential viral causes including enteroviruses, EBV, and other herpes viruses have hit the headlines from time to time, but so far the evidence is unconvincing. In 2009, researchers from the US examined over 100 CFS patients and reported finding a recently discovered mouse retrovirus called XMRV (or xenotropic murine leukaemia virus-related virus) in to induce immunity without severe" virus LEH approximately two-thirds of patients. This suggested that antiretroviral therapy could benefit CSF sufferers, but unfortunately the findings could not be repeated by scientists in the UK. This could mean that CSF in the US and UK has different causes, but for now the debate as to whether CSF has an infectious or psychological origin continues.
In addition to predicting and identifying ‘new’ infections, we can also expect virus discovery to continue apace in the 21st century. Using modern molecular technologies, it is likely that many diseases, including some cancers, will be identified as viral, leading to preventive vaccines and novel treatments. A few therapeutic vaccines designed to boost the anti-tumor virus immune response in people who already have a virus-associated tumor are already in clinical trials. And as our knowledge of immune interactions increases, more sophisticated manipulation of the immune response should be feasible, tipping the balance in favor of tumor destruction. In this regard, immunotherapy trials using a variety of tools including specific antibodies and T cells to target virus-infected tumor cells are giving promising results, and the hope is that where appropriate this more natural form of treatment might replace chemotherapy and radiotherapy regimens with their unpleasant side effects.
Interestingly, there are indications that, in addition to causing traditional infectious diseases, viruses also play a role in the causation of certain non-infectious, chronic diseases. Multiple sclerosis (MS) is a debilitating disease of the nervous system which generally affects young adults and runs a chronic, relapsing course. Progressive nerve damage is caused by autoimmune destruction of the myelin sheath that surrounds nerve fibers, slowing and distorting the impulses they carry. The trigger for the production of auto antibodies directed against the myelin protein is unknown, although both inherited and environmental factors are implicated.
The epidemiology of MS and glandular fever caused by EBV is quite similar in that both are most common among high socioeconomic groups in affluent countries. This suggests that, like glandular fever, MS may be triggered by a delayed primary infection with an unknown virus. Indeed, MS is significantly more common in those who have suffered from glandular fever, and evidence is accumulating for a direct link between EBV and MS.
This is difficult to prove because almost everyone is infected with EBV but only a very small minority develop MS. However, recent studies show that whereas over 99% of adults with MS are infected with EBV, the level in matched, healthy control groups is around 90%. This means that an EBV-negative person is extremely unlikely to develop MS, but exactly why this should be, and whether EBV is causally linked to MS, remains unclear. Another example is the herpes virus cytomegalovirus (CMV), found as a persistent infection in approximately 50% of the developed world’s population, which has been linked to coronary heart disease. The virus can be found in athermanous plaques in diseased arteries where the chronic inflammation it causes may contribute to the subsequent blockage of blood flow that precipitates a heart attack. Another novel finding is that among the elderly, those with persistent CMV infection die earlier than those without. This is thought to be due to the long-term accumulation of CMV-specific immune T cells that in old age literally leave no room for an adequate immune response to other infectious agents.
These intriguing associations certainly warrant further investigation. As we have seen with cancer, although viruses may represent only one link in the chain of events that leads to a disease, their removal could to induce immunity without severe" virus LEH prevent the disease occurring. These indirect effects of herpes viruses encourage some to think that several of our persistent viruses at present considered harmless may contribute to other common disorders.
During this century, we can look forward to man-made threats that in the worst-case scenario may impact on our burden of virus infections.
The idea of using microbes as weapons of mass destruction has been around for a long time, and the fact that it was prohibited by the Geneva Protocol of 1925 did not stop several countries running extensive programmes to develop and test the best candidates. Even the Biological Toxic Weapons convention of 1975 failed to halt this activity entirely, and nowadays the main threat is from terrorist groups.
The release of anthrax bacillus in the US in the aftermath of 9/11 certainly focused the world’s attention on the threat posed by biological weapons, and some Western governments have since stockpiled the necessary drugs and vaccines to counteract such an attack. Although the rumours of biological weapons in Saddam Hussein’s Iraq turned out to be false, in 2003’s Operation Iraqi
Freedom, troops went into battle vaccinated, wearing protective clothing, and swallowing antibiotics – thought by some to be the cause of ‘Gulf War syndrome’.
Since they are relatively cheap and easy to prepare in factories masquerading as vaccine-production plants, the worry is that deadly microbes can be manufactured by terrorist groups. Their use would be difficult to detect in time to prevent a full-scale disaster as they are invisible, odourless, tasteless, often stable, effective in tiny quantities, and easily transportable across international frontiers without detection. They have the potential for targeted attacks, and broader application affecting large populations. Their delayed action allows the perpetrator time to escape. Several viruses feature in the list of potential threats, with Ebola and smallpox viruses being among the most deadly. Other viruses could be used to debilitate populations as opposed to killing them. Viruses such as rotavirus, causing diarrhoea and vomiting, could certainly weaken a population, but should be treatable.
Ebola virus poses a great threat, particularly in small communities, due to it being highly infectious; easily spread from person to person, with high mortality rates. Ebola outbreaks are usually self-limiting because of the necessity for direct spread: the short incubation period, and the devastating symptoms prevent sufferers from travelling far from the scene. Thus, as soon as the chain of infection is broken by barrier nursing, the outbreak can be controlled.
The situation would be entirely different with a virus like smallpox, phials of which are kept in two high-security laboratories, one in the US and the other in Russia. Some suspect that virus stocks may have been raided during political upheavals accompanying the break-up of the Soviet Union and could in theory have got into the hands of terrorist groups. The incubation period for smallpox is 12 to 24 days, which would enable worldwide dissemination before the first cases emerged. The virus, if released, could be devastating as it is easily spread, is stable, and requires just one or two particles to infect a person. This threat has led some governments to stockpile smallpox vaccine for just such an eventuality, but in reality it would be impossible to vaccinate a whole population in time to stop a pandemic. People vaccinated before the eradication campaign ended in 1977 may still be immune, but the majority of the world’s population would be susceptible and the death rate likely to be around 30%.
