There are two broad classes of viruses, DNA viruses and RNA viruses. DNA viruses carry their genomic information in the form of DNA, just like we do. The herpesviruses are examples of DNA viruses. RNA viruses carry their genomic information in the form of RNA. Viruses that cause common childhood diseases like measles, mumps, and rubella are RNA viruses, as are the ones that cause influenza, AIDS, and the COVID-19 disease. RNA and DNA viruses hijack the host cell’s machinery in different ways to replicate.
Once a virus enters a cell, its DNA or RNA genome is released into the cell. The DNA genome of DNA viruses enters the cell’s nucleus. Now, new viral proteins are made using the host cell’s machinery in the same way that our own DNA is translated into our own proteins. First, some viral genes are transcribed to the corresponding RNA molecules, and then these are translated into some “early” viral proteins. Along with the host cell’s machinery, these early proteins help translate the rest of the virus’s DNA into a complete set of viral proteins. These proteins are then assembled into new virus particles, which then exit the cell and search for new cells to infect. Sometimes, the host cell dies during this process.
Once inside the cell, RNA viruses need to make many copies of their RNA genome, which can then be translated into many viral proteins, which are assembled into new virus particles. Most RNA viruses carry a molecule that makes copies of their own RNA. This molecule is called an RNA-dependent RNA polymerase. Once many copies of the virus’s RNA are available, the host cell’s protein-making machine, the ribosome, is used to translate the information in the RNA to the virus’s proteins. New virus particles are then assembled and they bud out of the cell.
While most RNA viruses replicate as described above, one type of RNA viruses does it differently. These viruses, for example, HIV, are called retroviruses. Retroviruses first convert their RNA into the corresponding DNA sequence. This is accomplished by a protein that the virus carries with it, called reverse transcriptase. The viral DNA then enters the cell’s nucleus, and a viral protein called integrase makes a nick in the host cell’s DNA and inserts the virus’s DNA there. Now, the host cell’s genome is altered forever, as it contains this piece of viral DNA. Using the host cell’s machinery, the virus’s DNA is then translated into its proteins, enabling the assembly of many new virus particles that go on to infect new cells. Until the mechanism by which retroviruses replicate was discovered, it was believed that the only way that genomic information was translated into proteins was by following the central dogma—DNA to RNA to proteins. Retroviruses translate their genomic information to proteins by the route, RNA to DNA to RNA to protein. For their paradigm-shifting discovery of how retroviruses replicate, David Baltimore and Howard Temin were awarded a Nobel Prize in 1975.
Retroviruses were first identified as tumor-causing viruses in animals. Whether they played any role in human cancer or any other human disease was not clear until the 1980s when a retrovirus was identified as the cause of a rare leukemia. Subsequently, HIV, a retrovirus, was found to be the causative agent of AIDS. When the human genome was first sequenced, a big surprise was that a large percentage of our DNA genome was comprised of retrovirus genes. These genes are usually not translated into proteins. This tells us that we have waged war with retroviruses for a long time, and they are hiding in our DNA. Understanding whether the retrovirus genes in our genome are implicated in cancer and how they impacted evolution of the human species is an active area of research.
RNA Viruses Can Change Guise Rapidly
When our cells translate the information in our DNA genomes into corresponding RNA and then into proteins, very few errors are made. RNA-dependent RNA polymerase, however, makes mistakes at much higher rates when it copies an RNA virus’s RNA. Similarly, reverse transcriptase makes many errors when it creates a DNA molecule from a retrovirus’s RNA genome. So, the proteins of RNA viruses that are made in a host cell often have a variety of amino acid sequences that are different from the proteins of the virus that originally infected the cell. Most such mutations result in defective proteins that prevent the new virus from functioning. But some mutations allow the virus to function just as well, and some even better. Thus, RNA viruses have an ability to change guise quickly and still function. Sometimes, they can even evolve new functions.
Using Genomic Information to Test for Viral Infection
During an ongoing epidemic or pandemic, it is very important to be able to rapidly identify infected people. These are the people who need to be isolated from others. To detect the virus, we need to know its RNA or DNA sequence. Once we know the sequence, a standard method called polymerase chain reaction (PCR) can be used to detect whether a sample of human fluid contains the virus that is the causative agent of a disease. PCR is a simple, ingenious idea for which its inventor, Kary Mullis, won a Nobel Prize. It takes advantage of a small synthetic DNA fragment called a primer that is designed to bind to the specific viral DNA or RNA sequence. If the RNA or DNA sequence specific to the primer is present, addition of a DNA polymerase allows a double-stranded fragment of DNA to be made. Doing this repeatedly many times amplifies this DNA fragment, and when there are many copies of DNA, it is easy to detect. This enables highly sensitive detection of rare DNA or RNA sequences. A few days after the RNA sequence of the virus that causes COVID-19 was published, Christian Drosten in Germany published a PCR method for detecting this virus. Implementing this method only required ordering a set of primers, and it was rapidly adopted by most countries around the world. However, the Centers for Disease Control and Prevention (CDC) in the United States decided to design its own test, which delayed the introduction of testing in that country.
Examples of RNA Viruses and Why They Cause Pandemics
In this section, we describe three examples of RNA viruses that have caused pandemics in the last century, and how the pandemic-causing viruses emerged.
SARS-CoV-2
Coronaviruses are a family of RNA viruses, and for years, four different types of these viruses have circulated in the human population. Some of them are among the many types of viruses that cause the common cold. No one pays much attention to them because these viruses cause mild disease symptoms in the vast majority of people whom they infect. They are basically just a nuisance.
In 2003, many patients in China were found to be suffering from acute respiratory distress syndrome that was caused by severe lung damage. Soon it was determined that the disease was due to a new type of coronavirus. The virus was called severe acute respiratory syndrome coronavirus, or SARS-CoV. The virus started spreading across East Asia to Hong Kong and Singapore, and then to Canada. SARS-CoV was deadly, resulting in the deaths of about 10 percent of those infected. Strong public health measures in China and other countries were ultimately able to control the SARS epidemic. About a decade later, in 2012, a virus emerged from Saudi Arabia that spread around the world, but mainly to South Korea. It too caused a severe respiratory illness, which was called Middle East respiratory syndrome (MERS). The causative agent was again a coronavirus. This virus was even more lethal than SARS, killing about 35 percent of those that it infected. Again, strict public health measures were able to extinguish MERS.
In late December 2019, physicians in Wuhan, China, began to suspect that a new virus was responsible for a flu-like respiratory disease. On January 10, 2020, Chinese officials announced that a new coronavirus caused this disease, and published its RNA sequence. The sequence was more similar to the virus that caused SARS than the one that caused MERS. In late January, almost on the same day, South Korea and the United States both detected patients who tested positive for the novel coronavirus. Within months, the virus would spread around the world, resulting in the death of hundreds of thousands of people. In response to the fast-spreading pandemic, countries around the world shut down their economies to keep people apart. The cost of this worldwide economic catastrophe is measured in many trillions of dollars, and millions have lost their jobs. The novel coronavirus that devastated the w
orld came to be called SARS-CoV-2, and the disease it causes, coronavirus disease of 2019 (COVID-19).
Why do new viruses cause pandemics or epidemics? How do these new pandemic- or epidemic-causing viruses emerge? Why did SARS and MERS not spread around the world, while COVID-19 became a global pandemic? Let us consider these questions in turn.
When a virus has been circulating in the human population for a while, most people have some level of immunity to it. So, they can fight the virus adequately, and only a few people become ill. When a totally new virus emerges, no one has immunity to this virus. So, the virus can infect anyone, and if the virus is easily transmitted, infected people can spread the virus to many others they encounter. If the virus also causes a lethal disease, a frightening pandemic can result. The coronaviruses that caused SARS, MERS, and COVID-19 were such new viruses to which humans were not immune.
How did these new coronaviruses arise? As we discussed earlier, RNA viruses mutate, and this provides them with a mechanism to change guise and evade human immunity. Did new coronaviruses, like SARS-CoV-2, evolve from mutations in the coronaviruses that circulate in humans and cause mild diseases, like the common cold?
To illustrate a point pertinent to this question, let us consider an RNA genome with 10 genes. Suppose that, due to errors made by RNA-dependent RNA polymerase, the chance of mutations arising in a gene when it is copied is one in five. On average, there will be mutations in two genes every time this RNA is replicated. If the RNA genome had 20 genes, there would be 4 mutations, if it had 80 genes, there would be 16 mutations, and so on. So, an RNA virus with a longer genome should have mutations in more genes. Compared with other RNA viruses, coronaviruses have a very long RNA genome. But when we peer at RNA sequences of these viruses, we do not see many mutations. Indeed, SARS-CoV-2 also has not mutated very much since it was first identified. Why is this?
Genes encode information about proteins that have to work together to enable a virus to function. Mutations make a protein different, which is likely to make it less compatible for working with other proteins. The larger the number of proteins with mutations, the more difficult it will be for viral proteins to work together, increasing the chance that the mutant viruses will not be viable. So, coronaviruses, with their long RNA genomes, would produce many progeny that would likely not function because of replication errors made by RNA-dependent RNA polymerase in many of its proteins. This is why coronaviruses have a protein that serves as a proofreader, like the one our cells have for DNA replication. So, if a wrong base is inserted as a new RNA strand is being created, the proofreader can excise it and the error is corrected. This is why coronaviruses mutate less than expected. The spikes of most coronaviruses that circulate in humans and cause mild disease do not bind to ACE2 (the receptor for SARS-CoV and SARS-CoV-2). They enter cells by binding to a completely different receptor. In order to bind to ACE2, many new mutations would have to arise in their spike proteins. Thus, since coronaviruses have a proofreader, it is unlikely that mutations in the common human coronaviruses led to the emergence of SARS-CoV or SARS-CoV-2.
Some families of viruses not only infect humans but can also infect and propagate in animals. For example, coronaviruses also infect rodents and bats. Although these viruses share some features with the human coronaviruses, their proteins are different in important ways. These differences usually make it difficult for a member of a virus family that thrives in a particular animal to do so in humans. Why this is so is explained by Darwin’s theory of how species evolve to adapt to their surroundings. Darwin’s studies showed that organisms mutate randomly. Most mutants are likely to be less adapted to their environment than their parent. If by chance a mutation arises that is better adapted to the environment than the parent, it slowly outcompetes the older species and becomes dominant in the population. In an analogous manner, mutations arise over time in coronaviruses that infect bats, for example, and they become better adapted for multiplying in bats. But these changes make the coronaviruses that infect bats less suitable for thriving in humans because we are a different environment.
However, every now and then, changes can occur in a virus that allow it to jump from being a virus that thrives in an animal to one that can productively infect humans. Often, this jump occurs in stages. For example, a bat coronavirus through a few mutations could become capable of infecting another animal. Also, bats can harbor many types of coronaviruses at the same time, and so two different coronaviruses could coexist in an infected cell. The two viruses could swap pieces of their genomes with each other to create a new hybrid virus that can infect another animal or a human. This process wherein the genomes of two viruses mix is called recombination. If the new hybrid bat virus infects an intermediate animal, it could acquire a couple of additional mutations therein that makes it thrive better in humans. This is especially likely to be true if the intermediate animal shares some traits with humans. SARS, MERS, and COVID-19 are diseases that were almost surely caused by viruses that jumped from bats to us, perhaps through intermediate animals.
During the first SARS epidemic, it was first thought that SARS-CoV was passed to humans by civets. These are small, cat-like animals that were being sold at live animal markets in southern China. There were documented examples of humans being infected by civets. But later it became clear that the SARS virus did not originate in civets. This initiated a worldwide search for the origin of the animal from which SARS-CoV jumped to humans. In 2005, working with an international consortium, Shi Zhengli, a Chinese virologist from the Wuhan Institute of Virology, identified coronaviruses in bats in China that were closely related to the SARS virus. This suggested that bats were the original source. Over the next 12 years, Shi traveled throughout China exploring bat caves. She collected and cataloged the coronaviruses that she found in bats throughout China. In 2017, she finally discovered what she was looking for. In a cave in southern China, she found a bat colony with viruses that were almost identical to the SARS virus, and were therefore its original source. Given her unusual devotion, the popular press dubbed her China’s “Bat Woman.”
When COVID-19 first emerged in China, Shi was urgently summoned home to Wuhan and she was the first to sequence and analyze the new virus. She reported that the new virus was related to the SARS virus, but, remarkably, it was almost identical to a bat virus that she had collected earlier. The major difference was in the proteins that made up the virus’s spike. The spike protein was very similar to that of a virus isolated from a pangolin, a small mammal with an armadillo-like shell. This suggested that the virus had passed from the bat to the pangolin before making the jump to humans. But this picture is uncertain, and will be clarified as more data become available. Whether this virus further adapted to thrive in humans after directly infecting humans, or whether it passed through an intermediate animal like a pangolin, is unclear.
SARS and MERS were lethal viruses, which rapidly killed many of those that it infected. But neither of these viruses caused global pandemics. Humans infected with these viruses quickly felt very sick with cough, fever, and malaise, and sought medical help. A virus that immobilizes infected people early in this way cannot spread too widely. This is because infected people largely come in contact only with close family members and healthcare professionals. So, it is relatively easy to contain the virus by isolating healthcare workers and close family members who came in contact with infected persons. This is how SARS was rather quickly eradicated. In the case of MERS, the virus jumped from bats to camels and then to humans. MERS infections occurred mainly in people with close contact with camels. All of these factors served to limit the spread of these two coronaviruses.
Comparing SARS-CoV and MERS with SARS-CoV-2 (the virus that causes COVID-19) reveals the kinds of features a virus needs to acquire in order to cause a worldwide pandemic. A person infected with SARS-CoV-2 can spread the virus to others before feeling any symptoms. Many infected people have mild or even no symptoms at all. So, infected people can move around a
nd infect many others before realizing that they are infected. This allows the virus to spread rapidly through populations. Although SARS and MERS have a higher fatality rate than COVID-19, the latter is deadly and kills about 1 percent of infected people. Because it infects many people and is quite lethal, SARS-CoV-2 has features that make it almost perfect for causing a deadly pandemic. The saving grace is that it does not mutate much, which would greatly complicate efforts to design a vaccine that can protect us from it (you will have to wait until later chapters to see why).
Influenza
Influenza is an RNA virus that is not a member of the coronavirus family of viruses. We are very familiar with influenza because it causes the seasonal flu, which like COVID-19 is a respiratory illness. Influenza has a relatively low rate of infectivity, but it can also be transmitted a few days before symptoms appear. Also, like COVID-19, a significant fraction of those infected do not feel very ill, which facilitates the spread of infection. Influenza clearly has a seasonal preference because cases peak in the Northern and Southern Hemispheres during their respective winters. Various factors are responsible for the seasonal preference. Some important factors are that people spend more time with each other in close proximity indoors when the weather is colder, and the virus survives better in cold, dry weather than in warm, humid weather.
The protein that makes up the viral spike of the influenza virus has a long name that is usually abbreviated as HA. Another important protein that is displayed on the surface of the virus is a protein whose name is abbreviated as NA. There are 18 different types of HA and 11 different types of NA. The different families of influenza viruses are classified by the specific combination of HA and NA that they have.
Viruses, Pandemics, and Immunity Page 5
