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  • Trying to Stop Long COVID Before It Even Starts

    Trying to Stop Long COVID Before It Even Starts

    Three years into the global fight against SARS-CoV-2, the arsenal to combat long COVID remains depressingly bare. Being vaccinated seems to reduce people’s chances of developing the condition, but the only surefire option for avoiding long COVID is to avoid catching the coronavirus at all—a proposition that feels ever more improbable. For anyone who is newly infected, “we don’t have any interventions that are known to work,” says Akiko Iwasaki, an immunologist and long-COVID researcher at Yale.

    Some researchers are hopeful that the forecast might shift soon. A pair of recent preprint studies, both now under review for publication in scientific journals, hint that two long-COVID-preventing pills might already be on our pharmacy shelves: the antiviral Paxlovid and metformin, an affordable drug commonly used for treating type 2 diabetes. When taken early in infection, each seems to at least modestly trim the chance of developing long COVID—by 42 percent, in the case of metformin. Neither set of results is a slam dunk. The Paxlovid findings did not come out of a clinical trial, and were focused on patients at high risk of developing severe, acute COVID; the metformin data did come out of a clinical trial, but the study was small. When I called more than half a dozen infectious-disease experts to discuss them, all used hopeful, but guarded, language: The results are “promising,” “intriguing”; they “warrant further investigation.”

    At this point, though, any advance at all feels momentous. Long COVID remains the pandemic’s biggest unknown: Researchers still can’t even agree on its prevalence or the features that define it. What is clear is that millions of people in the United States alone, and countless more worldwide, have experienced some form of it, and more are expected to join them. “We’ve already seen early data, and we’ll continue to see data, that that will emphasize the impact that long COVID has on our society, on quality of life, on productivity, on our health system and medical expenditures,” says Susanna Naggie, an infectious-disease physician and COVID-drug researcher at Duke University. “This needs to be a high priority,” she told me. Researchers have to trim long COVID incidence as much as possible, as soon as possible, with whatever safe, effective options they can.

    By now, news of the inertia around preventive long-COVID therapies may not come as much of a shock. Interventions that stop disease from developing are, on the whole, a neglected group; big, blinded, placebo-controlled clinical trials—the industry gold standard—usually look to investigate potential treatments, rather than drugs that might keep future illness at bay. It’s a bias that makes research easier and faster; it’s a core part of the American medical culture’s reactive approach to health.

    Read: Long COVID has forced a reckoning for one of medicine’s most neglected diseases

    For long COVID, the terrain is even rougher. Researchers are best able to address prevention when they understand a disease’s triggers, the source of its symptoms, and who’s most at risk. That intel provides a road map, pointing them toward specific bodily systems and interventions. The potential causes of COVID, though, remain murky, says Adrian Hernandez, a cardiologist and clinical researcher at Duke. Years of research have shown that the condition is quite likely to comprise a cluster of diverse syndromes with different triggers and prognoses, more like a category (e.g., “cancer”) than a singular disease. If that’s the case, then a single preventive treatment shouldn’t be expected to cut its rates for everyone. Without a universal way to define and diagnose the condition, researchers can’t easily design trials, either. Endpoints such as hospitalization and death tend to be binary and countable. Long COVID operates in shades of gray.

    Still, some scientists might be making headway with vetted antiviral drugs, already known to slash the risk of developing severe COVID-19. A subset of long-COVID cases could be caused by bits of virus that linger in the body, prompting the immune system to wage an extended war; a drug that clears the microbe more quickly might lower the chances that any part of the invader sticks around. Paxlovid, which interferes with SARS-CoV-2’s ability to copy itself inside of our cells, fits that bill. “The idea here is really nipping it in the bud,” says Ziyad Al-Aly, a clinical epidemiologist and long-COVID researcher at Washington University in St. Louis, who led the recent Paxlovid work.

    Paxlovid has yet to hit the scientific jackpot: proof from a big clinical trial that shows it can prevent long COVID in newly infected people. But Al-Aly’s study, which pored over the electronic medical records of more than 56,000 high-risk patients, offers some early optimism. People who took the pills, he and his colleagues found, were 26 percent less likely to report lingering symptoms three months after their symptoms began than those who didn’t.

    Read: Inside the mind of an anti-Paxxer

    The pills’ main benefit remains the prevention of severe, acute disease. (In the recent study, Paxlovid-takers were also 30 percent less likely to be hospitalized and 48 percent less likely to die.) Al-Aly expects that the drug’s effectiveness at preventing long COVID—if it’s confirmed in other populations—will be “modest, not huge.” Though the two functions could yet be linked: Some long-COVID cases may result from severe infections that damage tissues so badly that the body struggles to recover. And should Paxlovid’s potential pan out, it could help build the case for testing other SARS-CoV-2 antivirals. Al-Aly and his colleagues are currently working on a similar study into molnupiravir. “The early results are encouraging,” he told me, though “not as robust as Paxlovid.” (Another study, run by other researchers, that followed hospitalized COVID patients found those who took remdesivir were less likely to get long COVID, but a later randomized clinical trial didn’t bear that out.)

    A clinical trial testing Paxlovid’s preventive potency against long COVID is still needed. Kit Longley, a spokesperson for Pfizer, told me in an email that the company doesn’t currently have one planned, though it is “continuing to monitor data from our clinical studies and real-world evidence.” (The company is collaborating with a research group at Stanford to study Paxlovid in new clinical contexts, but they’re looking at whether the pills  might treat long COVID that’s already developed. The RECOVER trial, a large NIH-funded study on long COVID, is also focusing its current studies on treatment.) But given the meager uptake rates for Paxlovid even among those in high-risk groups, Al-Aly thinks his new data could already serve a useful purpose: providing people with extra motivation to take the drug.

    The case for adding metformin to the anti-COVID tool kit might be a bit muddier. The drug isn’t the most intuitive medication to deploy against a respiratory virus, and despite its widespread use among diabetics, its exact effects on the body remain nebulous, says Stacey Schultz-Cherry, a virologist at St. Jude Children’s Research Hospital. But there are many reasons to believe it might be useful. Some research has shown that metformin can mess with the manufacture of viral proteins inside of human cells, Bramante told me, which may impede the ability of SARS-CoV-2 and other pathogens to reproduce. The drug also appears to rev up the disease-dueling powers of certain immune cells, and to stave off inflammation. Studies have shown that metformin can improve responses to certain vaccinations in humans and rodents, and researchers have found that people taking the drug seem less likely to get seriously sick from influenza. Even the diabetes-coronavirus connection may not be so tenuous: Metabolic disease is a risk factor for severe COVID; infection itself can put blood-sugar levels on the fritz. It’s certainly plausible that having a metabolically altered body, Schultz-Cherry told me, could make infections worse.

    Read: The promising treatment we’re not even trying for long COVID

    But the evidence that metformin helps prevent long COVID remains sparse. Carolyn Bramante, the scientist who led the metformin study, told me that when her team first set out in 2020 to investigate the drug’s effects on SARS-CoV-2 infections in a randomized, clinical trial, long COVID wasn’t really on their radar. Like many others in their field, they were hoping to repurpose established medicines to keep infected people out of the hospital; early studies of metformin—as well as the two other drugs in their trial, the antidepressant fluvoxamine and the antiparasitic ivermectin—hinted that they’d work. Ironically, two years later, their story flipped around. A large analysis, published last summer, showed that none of the three drugs were stellar at preventing severe COVID in the short term—a disappointing result (though Bramante contends that their data still indicate that metformin does some good). Then, when Bramante and her colleagues examined their data again, they found that study participants that had taken metformin for two weeks around the start of their illness were 42 percent less likely to have a long-COVID diagnosis from their doctor nearly a year down the road. David Boulware, an infectious-disease physician who helped lead the work, considers that degree of reduction pretty decent: “Is it 100 percent? No,” he told me. “But it’s better than zero.”

    Metformin may well prove to prevent long COVID but not acute, severe COVID (or vice versa). Plenty of people who never spend time in the hospital can still end up developing chronic symptoms. And Iwasaki points out that the demographics of long-haulers and people who get severe COVID don’t really overlap; the latter skew older and male. In the future, early-infection regimens may be multipronged: antivirals, partnered with metabolic drugs, in the hopes of keeping symptoms both mild and short-lived.

    But researchers are still a long way off from delivering that reality. It’s not yet clear, for instance, whether the drugs work additively when combined, Boulware told me. Nor is it a given that they’ll work across different demographics—age, vaccination status, risk factors, and more. Bramante and Boulware’s study cast a decently wide net: Although everyone enrolled in the trial was overweight or obese, many were young and healthy; a few were even pregnant. The study was not enormous, though—about 1,000 people. It also relied on patients’ individual doctors to deliver long-COVID diagnoses, likely leading to some inconsistencies, so other studies that follow up in the future could find different results. For now, this isn’t enough to “mean we should run out and use metformin,” Schultz-Cherry, who has been battling long COVID herself, told me.

    Other medications could still fill the long-COVID gaps. Hernandez, the Duke cardiologist, is hopeful that one of his ongoing clinical trials, ACTIV-6, might provide answers soon. He and his team are testing whether any of several drugs—including ivermectin, fluvoxamine, the steroid fluticasone, and, as a new addition, the anti-inflammatory montelukast—might cut down on severe, short-term COVID. But Hernandez and his colleagues, Naggie among them, appended a check-in at the 90-day mark, when they’ll be asking their patients whether they’re experiencing a dozen or so symptoms that could hint at a chronic syndrome.

    That check-in questionnaire won’t capture the full list of long-COVID symptoms, now more than 200 strong. Still, the three-month benchmark could give them a sense of where to keep looking, and for how long. Hernandez, Naggie, and their colleagues are considering whether to extend their follow-up period to six months, maybe farther. The need for long-COVID prevention, after all, will only grow as the total infection count does. “We’re not going to get rid of long COVID anytime soon,” Iwasaki told me. “The more we can prevent onset, the better off we are.”

    Katherine J. Wu

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  • The Fatal Error of an Ancient, HIV-Like Virus

    The Fatal Error of an Ancient, HIV-Like Virus

    Many, many millions of years ago, an HIV-like virus wriggled its way into the genome of a floofy, bulgy-eyed lemur, and got permanently stuck.

    Trapped in a cage of primate DNA, the virus could no longer properly copy itself or cause life-threatening disease. It became a tame captive, passed down by the lemur to its offspring, and by them down to theirs. Today, the benign remains of that microbe are still wedged among a fleet of lemur genes—all that is left of a virus that may have once been as deadly as HIV is today.

    Lentiviruses, the viral group that includes HIV, are an undeniable scourge. The viruses set up chronic, slow-brewing infections in mammals, typically crippling a subset of immune cells essential to keeping dangerous pathogens at bay. And as far as scientists know, these viruses are pretty uniformly devastating to their hosts—or at least, that’s true of “all the lentiviruses that we know of,” says Aris Katzourakis, an evolutionary virologist at the University of Oxford. Which means, a long time ago, that lemur lentivirus was likely devastating too. But somewhere along the way, the strife between lemur and lentivirus dissipated enough that their genomes were able to mix. It’s proof, says Andrea Kirmaier, an evolutionary virologist at Boston College, that lentivirus and host “can coexist, that peace can be made.”

    Détentes such as these have been a fixture of mammals’ genomic history for countless millennia. Scientists have stumbled across lentiviruses embedded in the DNA of not just lemurs, but rabbits, ferrets, gliding mammals called colugos, and most recently, rodents—all of them ancient, all of them quiescent, all of them seemingly stripped of their most onerous traits. The infectious versions of those viruses are now extinct. But the fact that they posed an infectious threat in the past can inform the strategies we take against wild lentiviruses now. Finding these defunct lentiviruses tells us which animals once harbored, or might still harbor, active ones and could potentially pass them to us. Their existence also suggests that, in the tussle between lentivirus and host, the mammal can gain the upper hand. Lemurs, rabbits, ferrets, colugos, and rodents, after all, are still here; the ancient lentiviruses are not. Perhaps humans could leverage these strange genetic alliances to negotiate similar terms with HIV—or even extinguish the modern virus for good.

    When viruses assimilate themselves into animal genomes in a heritable way, a process called endogenization, scientists generally see it as “kind of a mistake,” says Daniel Blanco-Melo, a virologist at the Fred Hutchinson Cancer Center. Once cemented into one host, the virus can no longer infect others; much of its genome may even end up degrading over time, which is “certainly not what it evolved to do.” The blunders usually happen with retroviruses, which have RNA-based genomes that they convert into DNA once they enter cells. The flip allows the viruses to plug their genetic material into that of their host, which is then forced to manufacture its pathogen’s proteins alongside its own. Sometimes, a retrovirus will inadvertently stitch itself into the genome of a sperm or an egg, and its blueprints end up passed to its host’s progeny. If the melding doesn’t kill the animal, the once-pathogen can become a permanent fixture of the creature’s DNA.

    Over time, the human genome has amassed a horde of these viral hitchhikers. Our DNA is so riddled with endogenous retroviruses, ERVs for short, that they technically occupy more space in our genomes than bona fide, protein-manufacturing genes do. But on the long list of ERVs that have breached our borders, lentiviruses are conspicuously absent, in both our genomes and those of other animals; up until the mid-aughts, some scientists thought lentiviruses might not endogenize at all. It wasn’t a totally wonky idea: Lentiviruses have complex genomes, and are extremely picky about the tissues they invade; they’re also quite dangerous, not exactly the kind of tenant that most creatures want occupying their cellular real estate. Or perhaps, some researchers posited, lentiviruses were endogi-capable, but simply too young. If they had only begun infecting mammals within the past few hundreds of thousands of years, there might not have been time for such accidents to occur.

    Then, some 15 years ago, a team led by Katzourakis and Rob Gifford, an evolutionary virologist at the University of Glasgow, discovered an endogenous lentivirus called RELIK in the genomes of rabbits and then in hares, a hint that it had lodged itself in the animals’ mutual ancestor at least 12 million years before. In an instant, the lentivirus timeline stretched, and in the years since has kept growing. Scientists have now identified endogenous lentiviruses in a wide enough array of mammals, Gifford told me, to suspect that lentiviruses may have been a part of our history for at least 100 million years—entering our very distant ancestors’ genomes before the demise of the dinosaurs, before the rise of primates, before the land masses of North and South America kissed. “That tells us just how long virus and host have been connected,” Katzourakis told me. Through those eons, lentiviruses and the mammals they afflict have been evolving in concert—the pathogen always trying to infect better, the animal always trying to more efficiently head its enemy off.

    Knowing that lentiviruses are so deeply laced into our past can help us understand how other mammals are faring against the ones that are still around today. Two species of monkeys, sooty mangabeys and African green monkeys, have spent so much evolutionary time with a lentivirus called SIV—the simian version of HIV—that they’ve grown tolerant of it. Even when chock-full of virus, the monkeys don’t seem to suffer the severe, immunocompromising disease that the pathogen induces in other primates, says Nikki Klatt, a microbiologist and an immunologist at the University of Minnesota. The key seems to be in the monkeys’ ultra-resilient, fast-healing guts, as well as their immune systems, which launch more muted attacks on SIV, keeping the body from destroying itself as it fights. Such immunological shrugs could enable certain retroviruses to eventually endogenize, says Lucie Etienne, an evolutionary virologist at the International Center for Infectiology Research, in Lyon, France.

    Many mammals have also developed powerful tools to prevent lentiviruses from reproducing in their bodies in the first place—proteins that can, for instance, mess with viral entry or replication, or prevent new viral particles from busting out of already infected cells. Viruses, too, can mutate and evolve, far faster than animals can. That’s given the pathogens plenty of chances to counteract these defenses; HIV, for instance, has no trouble sidestepping or punching through many of the shields that human cells raise against it.

    Read: Could genetics be the key to never getting the coronavirus?

    But take the equivalent immune-defense protein from a monkey, and HIV “cannot degrade that,” says Michael Emerman, a virologist at the Fred Hutchinson Cancer Center. Other primates have had different infectious histories from ours, which have shaped their immune evolution in distinct ways. Studying those primates’ genomes—or maybe even the genomes of mammals that are carrying lentiviruses as neutered genetic cargo—might eventually inspire therapies that “augment our immunity,” Emerman told me. At the very least, such experiments could point scientists to lentiviruses’ common weak spots: the parts of the virus that ancient immune systems once targeted successfully enough that their hosts survived to tell the tale. “Evolution has already taught us the best places to target retroviruses,” says Maria Tokuyama, a virologist at the University of British Columbia. “Why not push for the types of interactions that we already know have worked?”

    Another, perhaps more radical idea might yet give way to an HIV cure: speeding the path toward endogenization—allowing lentiviruses to tangle themselves into our genomes, in the hopes that they’ll stay permanently, benignly put. “We could figure out a way to silence the virus, such that it’s there but we don’t care about it,” says Oliver Fregoso, a virologist at UCLA. One of the holy grails of HIV research has always been cooking up a vaccine that could prevent infection—an extraordinarily difficult thing to do. But if some sort of gentle armistice can be reached, Boston College’s Kirmaier told me, “maybe we don’t need to go that far.”

    Cedric Feschotte and Sabrina Leddy, virologists at Cornell, are among those pushing for such an intervention. They’re capitalizing on HIV’s tendency to go dormant inside cells, where it can hide from some of our most powerful antiretroviral drugs. The virus essentially “plays dead,” Leddy told me, then reawakens when the coast is clear. But if HIV could be silenced stably, its rampage would end when it jammed itself into the genome. “We’re hoping to emulate this natural path that ERVs have taken,” where they’re effectively locked in place, Leddy said. The imprisoned viruses could then be excised from cells with gene editing.

    The idea’s ambitious and still a way off from yielding usable treatments. But if it works, it could produce an additional perk. After setting up shop inside us, our viral tenants can start to offer their landlord benefits—such as fighting off their own active kin. In recent years, researchers have found that some animals, including cats, chickens, mice, primates, sheep, and even humans, have been able to co-opt proteins from certain endogenous retroviruses to create blockades against incoming viruses of similar ilk. Blanco-Melo and Gifford were part of a team that made one such discovery in 2017, describing an ERV that ancient monkeys and apes might have used to strip viral entryways off the surfaces of their cells. When encountering an ERV-ed-up host, the infectious, still-pathogenic version of that ERV would no longer have been able to get in.

    Eventually, the active retrovirus “just went extinct,” Blanco-Melo told me—an outcome that he thinks could be attributable to the antics of its endogenous counterpart. It’s a devious move, essentially a way to “turn the virus against itself,” Kirmaier said. This sort of friendly-fire tactic may already be at work among lentiviruses, duking it out inside and outside host genomes: Species with endogenous lentiviruses usually aren’t bedeviled by active lentiviruses, at least none that has been identified yet, Fregoso told me. With any luck, the same could someday be true for HIV, the virus little more than a memory—or an idle fragment in our cells.

    Katherine J. Wu

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