Tools & Technology

Going Viral

How do virologists stop something that is ubiquitous and deadly?

By Jacob Roberts | May 12, 2017

Is a virus alive? It’s a tough question, even for Joseph Rucker.

Rucker is vice president of R&D for Philadelphia biotech company Integral Molecular (and a sometimes contributor to CHF’s magazine). I know him because he was the instructor of a six-week course on the strange world of viruses that I attended this winter.

Long story short, Rucker says no, viruses are not alive. Why? Because they need to hijack a living cell to replicate. (Later in the class Rucker conceded that viruses might be considered alive after they have entered a cell and begun the process of replication. But that wasn’t even the strangest theory he relayed. Some scientists have suggested that viruses are inevitable byproducts of life; others have proposed that they are precursors of it. Traces of ancient viruses have been embedded in our DNA for at least hundreds of thousands of years. Perhaps viruses aren’t just in us; maybe they are us.)

Whatever the connection, all life on Earth has significantly diverged from viruses, even if we do share a few strands of DNA with them. As a simple pile of molecules, viruses cannot use or create energy the way plants, animals, and bacteria can. They have no way to move on their own and, left without air currents to push them or organisms to infect, will remain inert until they turn to dust. Depending on the virus, that process of decomposition might take a very long time. The majority of viruses are protected by a hard, outer shell of proteins that encases their genetic material (RNA or DNA), sort of like a microscopic nut. Disease-causing viruses, such as poliovirus and rhinovirus (the common cold), share this structure. Other viruses have an additional layer covering their outer shell, known as an envelope, which is usually made up of lipids (fat). Hepatitis C falls into that category, and looks a little bit like a nut inside a water balloon. There are plenty more viral structures out there, but the kinds that infect humans usually fall into one of those two categories.

Somehow, these inert balls of proteins, lipids, and DNA have become one of the most prolific things on Earth. They have no will or drive to reproduce, and yet they replicate just by floating around and randomly stumbling across cells to infect. How did they become so abundant with so many limitations? Throughout the course of Rucker’s class, the answer became clear: viruses work almost entirely due to their physical shape.

Imagine that an infinite number of burglars are lined up in front of a locked house, each with a different, randomly generated key. Eventually one of the burglars will be able to open the door. Membranes of living cells are like the locked doors, designed to let through only the proteins and lipids that are needed to keep cells alive. Viruses are like the burglars with infinite, randomly generated keys. Eventually a virus will show up that just so happens to have the correct protein receptor to get through a cell membrane.

Take the human immunodeficiency virus (HIV), an example Rucker often used in his lectures because the outbreak in the 1980s inspired him to research viruses in the first place. Although no one knows for sure when or where HIV first appeared, it might have jumped to humans centuries ago in remote villages in the interior of Africa, possibly multiple times. When people came into contact with the blood of the chimpanzees they were hunting for food, they were probably infected with simian immunodeficiency virus. But how did a simian virus turn into a human one?

HIV targets a type of protein called CD4 receptors, which live on the surface of white blood cells. CD4 receptors hang off the cell membrane like thick, curly hairs. Virologists theorize that a binding protein on the outer envelope of the chimpanzee virus randomly mutated to allow it to attach to CD4 in humans; a burglar stumbling across the right key. When a chimpanzee hunter got infected with early strains of HIV, the hunter would usually pass the disease on to others in their village, but the virus would reach a dead end after everyone infected with it died. That dynamic changed in the late 1800s when Europeans started colonizing Africa. Previously inaccessible villages on the edge of the wilderness were suddenly connected by road and rail to the coast, and the trafficking of humans and natural resources brought the few people infected with HIV into contact with the rest of the world. It took until the 1980s before it infected enough people to be noticeable on a global scale.

(When it comes to viruses, mutations can be good too. To hijack a cell, HIV requires the help of a coreceptor as well as CD4. Some people have a gene that twists these coreceptors into an unusual shape, which blocks HIV from binding to them properly and makes these people essentially immune to the disease.)

The mechanics of HIV are particularly interesting: once it comes across an available CD4 receptor, it gets reeled in and embeds what is called a fusion peptide into the cell membrane; like the virus is a sailor harpooning an enormous whale. The peptide then splits in half and the two new parts yank open a hole in the membrane, through which viral RNA is injected.

Once inside the cell, the metaphor changes. The RNA initiates what is essentially an automatic program that hijacks the cell’s equipment and adds the virus’s genetic code to the cell’s DNA. The result is that when the cell starts to replicate, instead of making a copy of itself, it makes more viruses.

So how do we stop HIV? One way may seem obvious: block or get rid of CD4 receptors. Unfortunately, those receptors are necessary for other cellular functions; blocking them would do more harm than good. Another method is to attack the programming that HIV uses to transcribe its genetic code into our cells.

The infamous drug AZT, developed in 1986, did exactly that. When the virus tried to turn its RNA into DNA, AZT was there to scramble the code into an unreadable mishmash of proteins. Initially, AZT was prescribed in doses that were so high they were toxic, often causing anemia and birth defects. Once doctors realized that the drug was just as effective at much smaller and safer doses, many found it to be a ray of hope in the face of exponentially rising mortality rates. But after a few months of treatment with AZT, HIV patients noticed something strange; their disease returned with a vengeance after being nearly wiped out. Not only that, but the reinfection was completely immune to AZT.

What happened? Virologists discovered that there were multiple strains of HIV living inside each individual person at the same time. Even without AZT meddling with the virus’s genetic transcription, HIV was very bad at making perfect copies of itself. Every time it replicated, it introduced multiple new errors and mutations. The vast majority of those mutations were detrimental and ended up killing off that particular strain of virus, but the few good mutations were so successful that they became completely immune to AZT.

The solution, which arrived in 1996, is to take a cocktail of different drugs that attacks all strains of HIV from different angles. In addition to messing with genetic transcription, new treatments also inhibit the virus’s connector protein that HIV uses to latch on to cells. With so many drugs working together, it is very unlikely that any one virus will randomly mutate an immunity to all of the drugs at once. The result is that nowadays people with HIV, if they adhere to their drug regimen, can lead a pretty normal life.

Of course, not everyone can afford drugs that cost hundreds of thousands of dollars over a lifetime, and only 18 million out of 37 million people living with HIV globally were receiving antiretroviral therapy in 2016, according to the World Health Organization.

Rucker noted that virologists are always in a race with the viruses they are trying to stop. Even as you are reading this blog post, a virus is probably mutating to resist the vaccine or antiviral drug designed to stop it. The HIV epidemic has shown that viruses are only going to become more ubiquitous as globalization creates the opportunity for them to move around the world and change faster than at any previous time in history. Thankfully, scientists are working tirelessly to better understand the physical processes of how viruses interact with our cells and create drugs that interrupt those processes, including new research that might make individual cells “immune” to HIV. Likewise, globalization has the side effect of transferring scientific information around the world faster. Let’s hope Rucker and his colleagues can keep up.