Can We Gene-Edit Herpes Away?

Because the virus hides out deep in our bodies and stays there for life, a vaccine has eluded scientists for decades. But there may be another way


Gene editing, which uses «molecular scissors» to cut and replace pieces of DNA, could be key for curing herpes.
(RooM the Agency / Alamy)

By

Becky Little

smithsonian.com

an hour ago

To become a contestant on the reality show «The Bachelor,» you must first pass a stringent list of requirements. These include numerous psychological and medical tests. But there’s one thing that keeps a disproportionate number of prospective contestants off the show and its sister show, «The Bachelorette,» at least according to the new book Bachelor Nation: herpes.

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In fact, many people only discover they have the sexually transmitted infection, or STI, once they apply for the reality show. That’s unfortunate, but it also isn’t surprising: The fact is, almost everyone has herpes.

Just so we’re defining our terms, genital herpes refers to the incredibly common STI caused by either type one or type two of the herpes simplex virus, or HSV. More than one in six people in the U.S., ages 14 to 49, have HSV-2. That works out to over 50 million Americans. Moreover, most people with this type of herpes don’t know they have it, because they experience only mild outbreaks or no outbreaks at all. An estimated 87 percent of people with HSV-2 haven’t received a clinical diagnosis, according to the Centers for Disease Control.

Being outbreak-free doesn’t mean you’re out of the woods. It’s true that outbreaks make it a lot more likely to transmit the virus to a partner, but people can also transmit the virus even if they have no symptoms, thanks to something known as asymptomatic shedding.

Around two-thirds of humans are infected with at least one of these two types of herpes, HSV-1 and HSV-2. And with both, once the virus enters your system, it’s there for life. For some, the infection causes painful, chronic outbreaks of genital lesions that interfere with their health and sexuality. Open sores also increase the risk of contracting HIV, intensify health problems for people who already have HIV, and can lead to fatalities in newborns. An increasing number of people are also HSV-1 on their genitals, often transmitted through oral sex.

So you can see why scientists have been trying to find a vaccine for herpes since the 1930s (billionaire Peter Thiel is funding one such venture). However, for now, none of the four major viral STIs—HIV, hepatitis B, HPV, and herpes—have a cure. But there’s one treatment that many scientists hope will be able to address some or all of them: genome editing.

Social Stigma

Direct health impacts aren’t the only reason scientists are so urgently looking for a herpes cure. Misconceptions about hygiene, sexuality and morality mean that, even today, herpes comes with society’s judgment. “I wouldn’t belittle the social stigma … and the psychological burden of it,” says Lesia K. Dropulic, the principal investigator of a recent herpes vaccine trial at the National Institute of Allergy and Infectious Diseases.

Testing positive for herpes carries the added stress of how a potential sexual partner will react when you disclose your infection. Wearing condoms, taking antiviral medication daily and avoiding sex during outbreaks can decrease the risk of transmission. But no sex is risk-free. For many, sex with herpes can still cause feelings of guilt that you are putting your partner at risk. “I’ve met a lot of people who really care and don’t want to give [herpes] to someone else,” Dropulic says.

Herpes activist Ella Dawson has written about the first time she had sex after being diagnosed with genital herpes. Even though she and her partner used a condom, and she was taking an antiviral medication to decrease the risk of transmission, Dawson still worried about the risk. “Could I really keep him safe?” she writes. “How would he react if the worst happened? Would he be as cruel as my ex?” After all, her ex had responded to her herpes diagnosis by calling her a “whore” and remarking, “this is what I get for falling for a girl like you.”

Because of both its physical and psychological tolls, scientists have spent decades trying to create a vaccine for herpes. But so far, the most successful medical advancements have been in antiviral medications that lower the chance of outbreaks and transmission.

Antivirals like acyclovir (Zovirax), introduced in 1982, and valacyclovir (Valtrex), approved in 1995, have reduced mortality rates in newborns with herpes from 80 to 10 percent. Both oral medications work by blocking the enzyme that herpes uses to copy itself and spread to other cells. This decreases viral shedding—i.e. the viral release that can cause lesions and infect others—but it can’t eliminate the latent virus that keeps herpes alive in your body. In other words, antivirals address the symptoms of herpes, but not the cause.

Here, gene editing might have a key advantage. But to understand why genome editing could be such a promising route forward, first you have to understand what makes herpes so hard to beat in the first place.

A Tenacious Virus

Biologically, herpes is impressive. The reason the virus sticks around for life is because it’s learned to hide out deep in our central nervous system, cleverly evading our immune system. With oral herpes, HSV-1 hangs out in the trigeminal ganglion, a nerve cluster in your skull. With genital herpes, both HSV-1 and HSV-2 hunker down next to your spine in the dorsal root ganglia.

At any time—usually after the immune system is compromised in some way—this latent infection can reactivate, causing an outbreak.

“So what they [HSV-1 and HSV-2] do is they infect skin [cells] and then they quickly end up going into a neuron, a nerve cell,” Dropulic explains. There, the virus “establishes a permanent infection.” Your immune system can’t recognize this kind of latent infection, and even if it could, to attack it would mean attacking its own nerve cells—which would cause severe side effects. In addition, the virus has “a number of proteins it uses to inhibit our immune system,” Dropulic adds.

Although we’ve known about this property of herpes for decades, researchers have never been able to safely and effectively target these cells. In fact, most experimental herpes vaccines either seek to prevent infection in people without herpes, or suppress viral shedding in people who already have it. Like your immune system, vaccines can’t target latent, hiding herpes without risking nerve damage.

Enter: gene editing. This powerful procedure works by introducing a human-made enzyme that “snips” genes at crucial points, and can then modify them or insert different segments in their stead. By potentially eliminating inherited diseases embedded in a person’s genetic makeup, scientists hope the procedure could one day help people who’ve been infected with otherwise incurable viruses like herpes and HIV.

“In gene editing, we have these sort of new and almost science-fiction seeming designer proteins that sometimes people call ‘molecular scissors,’” says Keith Jerome, a virologist at at
Fred Hutchinson Cancer Research Center who co-authored a 2016 study in the journal JCI Insight about gene editing in herpes-infected mice. His is the first study to show that gene-editing technology can reach the latent virus in a nerve cell, and the first to use that technology to damage some of the virus’ DNA.

In Jerome’s research, molecular scissors enter a cell and look for a specific sequence of DNA that is only found in the herpes virus. Once they find the herpes-specific DNA, the scissors cut it in half. This disrupts the virus so that “it’s no longer able to reactivate, cause lesions, transmit to a new host, any of those problems,” he says.

Granted, the gene-editing technology used in Jerome’s study was only able to reach enough DNA to deactivate a small fraction of the virus in mice—about 2 to 4 percent. However, it’s possible that efficient gene-editing technologies like CRISPR could do more. “If we can perfect it in the future studies, this would be a way to completely inactivate all the virus in a person,” he says. Jerome’s lab continues to study how to use gene editing to treat herpes, as well as HIV, hepatitis B and HPV.

Snipping Disease Away?

Cutting into people’s DNA is a much more direct route than previous vaccine efforts have taken, even the most innovative ones. The immunotherapy company Genocea Biosciences created its GEN-003 herpes vaccine by studying the T-cells of people who had been infected with herpes, then comparing them to people who had been exposed but not infected. Using this information, it created a vaccine that it hoped would help most people’s T-cells recognize proteins in the herpes virus in order to fight it, says Jessica Flechtner, the chief scientific officer at Genocea.

The trials found that in people who had genital herpes, the vaccine was able to reduce viral shedding. But for some of the medical community, the vaccine didn’t reduce it enough.

Because the vaccine didn’t appear to work better than valacyclovir, the go-to medicine for managing herpes outbreaks, Josh Bloom of the American Council on Science and Health writes that it “would seem to have an uphill battle” getting it approved. Right now, the vaccine won’t be able to move forward with FDA trials unless it secures funding from a corporation.

Still, scientists studying gene editing emphasize that vaccine research remains an important part of tackling the herpes challenge. Most research regarding gene editing and herpes, for example, only focuses on therapeutic treatment meant for people who already have herpes. But what about people who want to protect themselves from getting the virus in the first place?

“A vaccine can prevent an infection, genome-engineering probably not,” writes Robert Jan Lebbink, a professor of medical microbiology at University Medical Center in Utrecht who is studying gene editing as a therapeutic herpes treatment, in an email. “Development of vaccines to prevent/limit herpes virus infections remains a major goal and should be continued.”

One possible preventative treatment on the horizon is a herpes vaccine containing some inactive parts of the virus designed by Harvey M. Friedman, a professor of medicine at the University of Pennsylvania. This vaccine, which is currently awaiting human trials, contains two proteins that the herpes virus uses to evade our immune systems. Friedman hopes that the vaccine will teach the body to recognize these proteins so it can combat a herpes virus if it ever encounters it.

Yet Friedman also acknowledges that a vaccine by itself might not be effective against herpes; scientists may have to develop combined treatments. As an example he points to the work of Akiko Iwasaki, a professor of immunobiology and molecular, cellular and developmental biology at Yale University. Iwasaki has been working on a “prime and pull” method that would use a vaccine and topical application to gather activated T-cells in the right place.

Jerome, too, thinks the future of herpes treatment lies in complementary treatments. “The perfect world would be: We have a cure through gene editing so the people who are infected now and having trouble with the virus can be cured and be free of those problems; and our vaccine folks come up with an effective vaccine that prevents new infection,” he says. “That would be the perfect outcome. So I hope that that’s what happens.”

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