Viruses are tiny and sneaky.
So sneaky that some play a deadly game of hide and seek. The “search” part is all too familiar: they're always looking for ways to infect people. Their ability to hide is much less known and can have devastating consequences.
The human body has several effective hiding places that have uncovered some of the world's most dangerous viruses – the eyes and testicles, for example – and which are beyond the reach of the immune system. This is where submicroscopic viral RNA can safely linger.
Often human hosts have no idea. They got sick and then seemed to beat the virus. Their blood test came back negative. They do not show any symptoms.
But this latent virus is capable of returning to action. It can come out of hiding—either by making the original host sick, or by passing into sperm or breast milk and infecting someone new.
What viruses have mastered this technique? A number of notorious viruses, from Zika to measles and deadly viruses such as Nipah, Marburg and Lassa fever.
And the virus that scared the world in 2014: Ebola.
In the decade since then, the Democratic Republic of Congo has seen more than its fair share of Ebola crises—nine outbreaks, including one ongoing—and more than its fair share of latent viruses coming back into play.
“Almost all of the recent outbreaks—maybe not all of them, but the vast majority—are linked to a previous outbreak,” said Dr. Elizabeth Higgs, a clinical research fellow at the National Institute of Allergy and Infectious Diseases. She says that after sequencing the genetics of the virus, it becomes clear that many outbreaks did not originate from an animal (such as a bat) but from a person who unwittingly carried the virus after surviving a previous outbreak.
Although most survivors will never start another outbreak, it happens often enough that Higgs said, “I think that's the main question in the research program.”
“Everyone was panicking”
Dr. Soka Moses first realized the significance of these viral havens ten years ago. It was mid-March 2015 when people in his West African country of Liberia breathed a collective sigh of relief.
The country was emerging from a nightmare, recalls Moses, then the medical director of the Ebola treatment center. About 5,000 people died last year. Some died on the streets, unable to find a hospital bed. Schools are closed, markets are closed.
Finally, in early March 2015, there were no more cases of Ebola.
But the crisis is not over.
Shortly after Liberia reached zero cases, Moses remembers sitting in a daily meeting led by Liberia's National Epidemic Response Team when “boom! A case has been identified.” When the rumors got out, he says, “Everyone was panicking: 'Oh my God.' Are we starting this again?”
Part of the panic was a mystery. How could this woman have contracted Ebola if there were no active cases? The virus spreads easily when someone comes into contact with an infected person's body fluids, even sweat or saliva, but it is unclear where or how this new patient may have become infected.
Family members eventually pointed out the woman's sexual partner to medical investigators. Five months ago he recovered from Ebola. “[He'd] on two different occasions the tests were negative,” says Moses.[He was] everything is fine, no symptoms.”
The man was scared and initially avoided the authorities. “He thought he was in really big trouble,” Moses says.
After making sure that he had no problems, he agreed to cooperate. The task for scientists: to find out whether the virus is hidden somewhere in his body.
They eventually determined that the Ebola virus was no longer in his blood… but continued to live in his testicles and was transmitted through his sperm.
“So it was sexually transmitted disease documented for the first time case of Ebola virus disease,” says Moses. Although he had read about a case in 1967 in which a different virus was lurking in the body, the consequences were now much clearer.
This prompted Moses to act. He is now the director of PREVAIL, or the Partnership for Research on Vaccines and Infectious Diseases in Liberia, which, among other things, studies the phenomenon of hidden viruses.
Sanctuaries of the body
Researchers have identified a number of places where viruses can hide – not just the eyes and testicles, but also the brain, placenta and vaginal secretions, and breasts.
“We call them sanctuary places,” says Joel MontgomeryDirector of the Division of Viral Special Pathogens at the US Centers for Disease Control and Prevention. For the virus, this is a refuge protected from the immune system.
Scientists believe this is likely because these parts of the body are critical for survival and are vulnerable to damage if the immune system overreacts.
For example, “in the process of creating eggs and sperm, we mix and match genes. So, in fact, they are no longer us,” says Dr. John SchieffelinAssistant Professor, Tulane University School of Medicine. This means that the immune system may perceive eggs or sperm as foreign invaders and try to attack them, so it is helpful if these parts of the body are kept out of reach of the immune system.
The brain has a special level of protection in the blood-brain barrier, which limits the penetration of immune cells. What about the eyes? “The optometrist might scold me for this, but to me it’s really an extension of the brain. There's a big nerve that goes from your eye straight to your brain,” Schieffelin says.
Lots of mysteries
Scientists still don't know much about how viruses behave in these shelters.
For example, how long can the virus stay there? In many cases where individuals have been tested, it appears to be a matter of months. In some cases this is years. There were even semen samples that tested negative for the virus at one point and then turned positive again. Scientists are unclear what caused this change. And researchers haven't followed people who have had one of these infections long enough to know the outer limit.
Another big unknown: what is the virus doing on the sanctuary grounds? It seems almost dormant, barely reproducing. “But we don’t know why someone relapses. We don't know if it's a decline in the immune system or if there's some other factor,” Montgomery says.
Fear and stigma
Montgomery says the goal is to find cures for survivors that can infiltrate refuge sites and eradicate any latent virus. According to him, the size of the drug molecule is key here.
“We really need to explore the use of small molecule drugs,” he says, suggesting that the smaller the drug molecule, the more likely it is to penetrate the protective barrier around the shelter.
Moses' team studied exactly this with the drug remdesivir—and the results were promising. Survivors who received the drug cleared their sperm of the virus faster than survivors who received a placebo.
Although many researchers focus on biology, the psychological part of the equation never leaves them. Ebola survivors can face intense fear and stigma.
When Dr. Dehkonti Dennis, who works for PREVAIL in Liberia, signed up for the study, she says she noticed “one thing that All of these men stated: “They have this fear.” They don't want to pass the virus on to their families. They want to have children. They want to stop using condoms [to prevent transmission]”
The flip side of their fear is that many community members who may have lost partners and other family members to Ebola fear that survivors could still pose a threat even if they don't know about shelter sites. “The community members didn't even want them to go back into the communities,” Moses says.
This level of stigma makes it difficult to talk about the risk that the virus could hide in a survivor and then resurface. Scientists say survivors and their communities should be aware that there is a possibility that this could happen, but only in a small percentage of cases.
Victim assistance programs that test sperm and vaccination campaigns to protect the public may also be a consolation. But scientists say the solution will be to find drugs that can detect these hidden, potentially deadly viruses.
“It's great that we have vaccines,” says Joel Montgomery of the Centers for Disease Control and Prevention (CDC). “It’s great that we have medicine. It's great that we save people's lives. But now we need to find a way to make sure the virus is completely eliminated from their lives.”
