Viruses are tiny — and sneaky.
So sneaky that some play a deadly game of hide and seek. The "seek" part is all too familiar: They're always looking for ways to infect humans. Their ability to hide is far less well-known and can have devastating implications.
The human body holds several effective hiding spots that some of the world's nastiest viruses have discovered — like the eyes and the testes — that are beyond the reach of the immune system. It's here that submicroscopic viral RNA can safely linger.
Often the human hosts have no idea. They'd fallen ill, then appeared to beat the virus. Their blood tested negative. They show no symptoms.
But that hidden virus is capable of springing back into action. It can emerge from hiding — either sickening the original host or slipping into semen or breast milk and infecting someone new.
Which viruses have mastered this technique? A number of notorious ones from Zika to measles to highly deadly viruses like Nipah, Marburg and Lassa fever.
And the virus that terrified the world in 2014: Ebola.
In the decade since, the Democratic Republic of Congo has experienced more than its fair share of Ebola crises — with nine outbreaks, including one that is ongoing — and more than its fair share of hidden viruses that spring back into action.
"Almost all the outbreaks recently — maybe not every single one of them but the vast majority — are traced back to a previous outbreak," says Dr. Elizabeth Higgs, who is with the Division of Clinical Research at the National Institute of Allergy and Infectious Diseases. She says once the genetics of the virus are sequenced it is clear that many of the outbreaks haven't come from an animal — like a bat — but from a human who unwittingly carried the virus after surviving a previous outbreak.
While most survivors will never start a new outbreak, it is happening enough that Higgs says, "I think it's top of the research agenda."
"Everybody was panicking"
Dr. Soka Moses first grasped the significance of these virus hideouts a decade ago. It was in mid-March 2015 when people in his West African country of Liberia were heaving a collective sigh of relief.
The country was emerging from a nightmare, recalls Moses, then the medical director at an Ebola treatment center. Nearly 5,000 people died over the previous year. Some perished in the streets, unable to find a hospital bed. Schools shuttered, markets closed.
Finally, in early March of 2015, there were no more Ebola cases.
But the crisis was not over.
Shortly after Liberia had reached zero cases, Moses recalls sitting in a daily meeting led by Liberia's National Epidemic Response Team when "boom! A case was identified." As word got out, he says: "Everybody was panicking: 'Oh, my God. Are we starting this again?'"
Part of the panic was the mystery. How could this woman have contracted Ebola when there were no active cases? The virus spreads easily when someone comes into contact with an infected person's bodily fluids, even sweat or saliva, but it was not clear where or how this new patient could have been exposed.
Family members eventually pointed medical investigators to the woman's sexual partner. Five months ago he'd recovered from Ebola. "[He'd] tested negative on two different occasions," says Moses. "[He was] doing perfectly fine, no symptoms whatsoever."
The man was terrified and, initially, avoided the authorities. "He thought he was in really big trouble," says Moses.
Once he was reassured that he was not in trouble, he agreed to cooperate. The challenge for scientists: Find out if the virus was hiding somewhere in his body.
They ultimately determined that the Ebola virus was no longer in his blood … but lived on in his testes and had been transmitted in his semen.
"So that was the first documented sexually transmitted case of Ebola virus disease," says Moses. While he'd read about a 1967 case in which another virus hid out in the body, the implications were now much clearer.
This prompted Moses to act. He's now the director of PREVAIL or the Partnership for Research on Vaccines & Infectious Diseases in Liberia, which studies the phenomenon of hidden viruses, among other things.
The body's sanctuary sites
Researchers have identified a number of spots where the viruses can hide — not only eyes and testes but also the brain, the placenta and vaginal fluids as well as the mammary glands.
"We call them sanctuary sites," says Joel Montgomery, chief of the Viral Special Pathogens Branch at the U.S. Centers for Disease Control and Prevention. For the virus, these are havens protected from the immune system.
Scientists think this is likely because these body parts are critical for survival — and vulnerable to damage if the immune system overreacts.
For example, "in the process of making eggs and sperm, we mix and match the genes. So they're not really us anymore," says Dr. John Schieffelin, an associate professor at Tulane University School of Medicine. That means the immune system might see eggs or sperm as foreign invaders and try to attack them, so it's helpful if those parts of the body are outside the reach of the immune system.
The brain has a special level of protection in the blood brain barrier which limits the entry of immune cells. As for the eye? "An eye doctor might scold me for this, but to me, it's really an extension of the brain. There's a large nerve that goes from your eye directly into your brain," Schieffelin says.
Many mysteries
There's still a lot scientists don't know about how viruses behave in these sanctuary sites.
For example, exactly how long can a virus stay there? In many cases where individuals were tested, it appears to be a matter of months. In some cases, it's years. There have even been semen samples that test negative for the virus at one point then return to positive later. It's not clear to scientists what prompted this reversal. And researchers haven't followed enough people who've harbored one of these infections long enough to know the outer limit.
Another big unknown: What is the virus doing in the sanctuary site? It seems as if it's almost dormant, barely replicating. "But we don't know why someone relapses. We don't know if it's a drop in their immune system or if there's some other factor," says Montgomery.
Fear and stigma
Montgomery says the goal is to identify medications for survivors that can reach into sanctuary sites and root out any hidden virus. For this, he says, the size of the molecule in the drug is key.
"We really need to explore the use of small-molecule drugs," he says, suggesting the smaller the drug's molecule the more likely it can penetrate the protective barrier around a sanctuary site.
Moses' team has been studying exactly this with the drug remdesivir — and results have been promising. Survivors who got the drug cleared the virus from their semen more quickly than survivors who got the placebo.
While many of the researchers are focused on the biology, something that's never far from their mind is the psychological part of the equation. Ebola survivors can face intense fear and stigma.
When Dr. Dehkontee Dennis — who works at PREVAIL in Liberia — was enrolling for the study, she says she noticed "there was one thing that all of these men have expressed: They have this fear. They don't want to transmit the virus 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 of the community members — who may have lost their partners and other family members to Ebola — fear the survivors may still pose a threat, even if they don't know about sanctuary sites. "Community members did not even want them back in the communities," says Moses.
This level of stigma makes it tricky to talk about the risk that the virus could hide in a survivor and then resurface. Survivors and their community need to know there's a chance this could happen, the scientists say — but only in a small percentage of cases.
Reassurance can also come from survivor programs that test semen and vaccination campaigns to protect the community. But scientists say the solution will be finding medications that can ferret out these hidden, potentially lethal viruses.
"It's great that we have vaccines," says Joel Montgomery of the CDC. "It's great that we have therapeutics. It's great that we're saving people's lives. But now we need to figure out a way to make sure the virus is completely eliminated from them."
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