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Tag: immune systems

  • One More COVID Summer?

    One More COVID Summer?

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    Since the pandemic’s earliest days, epidemiologists have been waiting for the coronavirus to finally snap out of its pan-season spree. No more spring waves like the first to hit the United States in 2020, no more mid-year surges like the one that turned Hot Vax Summer on its head. Eventually, or so the hope went, SARS-CoV-2 would adhere to the same calendar that many other airway pathogens stick to, at least in temperate parts of the globe: a heavy winter peak, then a summer on sabbatical.

    But three and a half years into the outbreak, the coronavirus is still stubbornly refusing to take the warmest months off. Some public-health experts are now worried that, after a relatively quiet stretch, the virus is kick-starting yet another summer wave. In the southern and northeastern United States, concentrations of the coronavirus in wastewater have been slowly ticking up for several weeks, with the Midwest and West now following suit; test-positivity rates, emergency-department diagnoses of COVID-19, and COVID hospitalizations are also on the rise. The absolute numbers are still small, and they may stay that way. But these are the clear and early signs of a brewing mid-year wave, says Caitlin Rivers, an epidemiologist at Johns Hopkins University—which would make this the fourth summer in a row with a distinct coronavirus bump.

    Even this far into the pandemic, though, no one can say for certain whether summer waves are a permanent COVID fixture—or if the virus exhibits a predictable seasonal pattern at all. No law of nature dictates that winters must come with respiratory illness, or that summers will not. “We just don’t know very much about what drives the cyclical patterns of respiratory infections,” says Sam Scarpino, an infectious-disease modeler at Northeastern University. Which means there’s still no part of the year when this virus is guaranteed to cut us any slack.

    That many pathogens do wax and wane with the seasons is indisputable. In temperate parts of the world, airborne bugs get a boost in winter, only to be stifled in the heat; polio and other feces-borne pathogens, meanwhile, often rise in summer, along with gonorrhea and some other STIs. But noticing these trends is one thing; truly understanding the triggers is another.

    Read: COVID sure looks seasonal now

    Some diseases lend themselves a bit more easily to explanation: Near the equator, waves of mosquito-borne illness, such as Zika and Chikungunya, tend to be tied to the weather-dependent life cycles of the insects that carry them; in temperate parts of the world, rates of Lyme disease track with the summertime activity of ticks. Flu, too, has pretty strong data to back its preference for wintry months. The virus—which is sheathed in a fragile, fatty layer called an envelope and travels airborne via moist drops—spreads best when it’s cool and dry, conditions that may help keep infectious particles intact and spittle aloft.

    The coronavirus has enough similarities to flu that most experts expect that it will continue to spread in winter too. Both viruses are housed in a sensitive skin; both prefer to move by aerosol. Both are also relatively speedy evolvers that don’t tend to generate long-lasting immunity against infection—factors conducive to repeat waves that hit populations at a fairly stable clip. For those reasons, Anice Lowen, a virologist at Emory University, anticipates that SARS-CoV-2 will continue to show “a clear wintertime seasonality in temperate regions of the world.” Winter is also a time when our bodies can be more susceptible to respiratory bugs: Cold, dry air can interfere with the movement of mucus that shuttles microbes out of the nose and throat; aridity can also make the cells that line those passageways shrivel and die; certain immune defenses might get a bit sleepier, with vitamin D in shorter supply.

    None of that precludes SARS-CoV-2 spread in the heat, even if experts aren’t sure why the virus so easily drives summer waves. Plenty of other microbes manage it: enteroviruses, polio, and more. Even rhinoviruses and adenoviruses, two of the most frequent causes of colds, tend to spread year-round, sometimes showing up in force during the year’s hottest months. (Many scientists presume that has something to do with these viruses’ relatively hardy outer layer, but the reason is undoubtedly more complex than that.) An oft-touted explanation for COVID’s summer waves is that people in certain parts of the country retreat indoors to beat the heat. But that argument alone “is weak,” Lowen told me. In industrialized nations, people spend more than 90 percent of their time indoors.

    That said, an accumulation of many small influences can together create a seasonal tipping point. Summer is a particularly popular time for travel, often to big gatherings. Many months out from winter and its numerous infections and vaccinations, population immunity might also be at a relative low at this time of year, Rivers said. Plus, for all its similarities to the flu, SARS-CoV-2 is its own beast: It has so far affected people more chronically and more severely, and has generated population-sweeping variants at a far faster pace. Those dynamics can all affect when waves manifest.

    And although certain bodily defenses do dip in the cold, data don’t support the idea that immunity is unilaterally stronger in the summer. Micaela Martinez, the director of environmental health at WE ACT for Environmental Justice, in New York, told me the situation is far more complicated than that. For years, she and other researchers have been gathering evidence that suggests that our bodies have distinctly seasonal immunological profiles—with some defensive molecules spiking in the summer and another set in winter. The consequences of those shifts aren’t yet apparent. But some of them could help explain when the coronavirus spreads. By the same token, winter is not a time of disease-ridden doom. Xaquin Castro Dopico, an immunologist at the Karolinska Institute, in Sweden, has found that immune systems in the Northern Hemisphere might be more inflammation-prone in the winter—which, yes, could make certain bouts of illness more severe but could also improve responses to certain vaccinations.

    All of those explanations could apply to COVID’s summer swings—or perhaps none does. “Everybody always wants to have a very simple seasonal answer,” Martinez told me. But one may simply not exist. Even the reasons for the seasonality of polio, a staunch summertime disease prior to its elimination in the U.S., have been “an open question” for many decades, Martinez told me.

    Rivers is hopeful that the coronavirus’s permanent patterns may already be starting to peek through: a wintry heyday, and a smaller maybe-summer hump. “We’re in year four, and we’re seeing the same thing year over year,” she told me. But some experts worry that discussions of COVID-19 seasonality are premature. SARS-CoV-2 is still so fresh to the human population that its patterns could be far from their final form. At an extreme, the patterns researchers observed during the first few years of the pandemic may not prelude the future much at all, because they encapsulate so much change: the initial lack and rapid acquisition of immunity, the virus’s evolution, the ebb and flow of masks, and more. Amid that mishmash of countervailing influences, says Brandon Ogbunu, an infectious-disease modeler at Yale, “you’re going to get some counterintuitive dynamics” that won’t necessarily last long term.

    Read: The next stage of COVID is starting now

    With so much of the world now infected, vaccinated, or both, and COVID mitigations almost entirely gone, the global situation is less in flux now. The virus itself, although still clearly changing at a blistering pace, has not pulled off an Omicron-caliber jump in evolution for more than a year and a half. But no one can yet promise predictability. The cadence of vaccination isn’t yet settled; Scarpino, of Northeastern University, also isn’t ready to dismiss the idea of a viral evolution surprise. Maybe summer waves, to the extent that they’re happening, are a sign that SARS-CoV-2 will remain a microbe for all seasons. Or maybe they’re part of the pandemic’s death rattle—noise in a system that hasn’t yet quieted down.

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    Katherine J. Wu

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  • A Major Breed of Flu Has Gone Missing

    A Major Breed of Flu Has Gone Missing

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    In March 2020, Yamagata’s trail went cold.

    The pathogen, one of the four main groups of flu viruses targeted by seasonal vaccines, had spent the first part of the year flitting across the Northern Hemisphere, as it typically did. As the seasons turned, scientists were preparing, as they typically did, for the virus to make its annual trek across the equator and seed new outbreaks in the globe’s southern half.

    That migration never came to pass. As the new coronavirus spread, pandemic-mitigation measures started to squash flu-transmission rates to record lows. The drop-off was so sharp that several flu lineages may have gone extinct, among them Yamagata, which hasn’t been definitively detected in more than three years despite virologists’ best efforts to root it out.

    Read: The pandemic broke the flu

    Yamagata’s disappearance could still be temporary. “Right now, we’re all just kind of holding our breath,” says Adam Lauring, a virologist at the University of Michigan Medical School. The virus might be biding its time in an isolated population, escaping the notice of tests. But the search has stretched on so fruitlessly that some experts are ready to declare it officially done. “It’s been missing for this long,” says Vijaykrishna Dhanasekaran, a virologist at Hong Kong University. “At this point, I would really think it’s gone.”

    If Yamagata remains AWOL indefinitely, its absence would have at least one relatively straightforward consequence: Researchers might no longer need to account for the lineage in annual vaccines. But its vanishing act could have a more head-spinning implication. Flu viruses, which have been plaguing human populations for centuries, are some of the most well-known and well-studied threats to our health. They have prompted the creation of annual shots, potent antivirals, and internationally funded surveillance programs. And yet, scientists still have some basic questions about why they behave as they do—especially about Yamagata and its closest kin.

    Yamagata, in many ways, has long been an underdog among underdogs. The lineage is one of two in a group called influenza B viruses, and it’s slower to evolve and transmit, and is thus sometimes considered less troublesome, than its close cousin Victoria. As a pair, the B’s are also commonly regarded as the wimpier versions of flu.

    To be fair, the competition is stiff. Flu B’s are constantly being compared with influenza A viruses—the group that contains every flu subtype that has caused a pandemic in our recent past, including the extraordinarily deadly outbreak of 1918. Seasonal flu epidemics, too, tend to be heavily dominated by flu A’s, especially H3N2 and H1N1, two notably tough-to-target strains that feature prominently in each year’s vaccine. Even H5N1, the flavor of avian influenza that’s been devastating North America’s wildlife, is a member of the pathogen’s A team.

    Read: Eagles Are Falling, Bears Are Going Blind

    B viruses, meanwhile, don’t have a particularly daunting résumé. “To our knowledge, there has never been a B pandemic,” says John Paget, an infectious-disease epidemiologist at the Netherlands Institute for Health Services Research. Only once every seven seasons or so does a B virus dominate. And although A and B viruses sometimes tag-team the winter, causing twin outbreaks spaced out by a few weeks, these seasons often open with a major flu A banger and then close out with a more muted B coda.

    The reasons underlying these differences are still pretty murky, though scientists do have some hints. Whereas flu A viruses are known as especially speedy shape-shifters, constantly spawning genetic offshoots that vie to outcompete one another, flu B’s evolve at oddly plodding rates. Their sluggish approach makes it easier for our immune system to recognize the viruses when they reappear, resulting in longer-lasting protection, more effective vaccines, and fewer reinfections than are typical with the A’s. Those molecular differences also seem to drive differences in how and when the viruses spread. The A’s tend to trouble people repeatedly from birth to death, and are great at globe-trotting. But B’s, perhaps because immunity against them is easier to come by, more often concentrate among kids, many of whom have never encountered the viruses before—and who are usually more resilient to respiratory viruses and travel less than adults, keeping outbreaks mostly regional. That might also help explain why B epidemics so frequently lag behind A’s: Slower pathogen evolution facing off with more durable host immunity add up to less rapid B spread, while their A colleagues rush ahead. Our bodies also seem to mount rather fiery defenses against A viruses, steeling them against other infections in the weeks that follow and deepening the disadvantage against any B’s trailing behind. All of that means flu B has a hard time catching humans off guard.

    The virus’s host preferences, too, make flu A viruses more dangerous. Those lineages are great at hopscotching among a whole menagerie of species—most infamously, pigs and wild, water-loving birds—sometimes undergoing rapid bursts of evolution as they go. But flu B’s seem to almost exclusively infect humans, igniting only the rare and fast-resolving outbreak in a limited number of other species—a few seals here, a handful of pigs there. Spillovers from wild creatures into humans are the roots of global outbreaks. And so, with its zoonotic bent, “influenza A will always be the main focus” of concern, says Carolien van de Sandt, a virologist at the Peter Doherty Institute for Infection and Immunity, in Melbourne. Even among some scientists, Yamagata and Victoria register as little more than literal B-list blips.

    Plenty of other experts, though, think flu B’s relative obscurity is misguided—perhaps even a bit dangerous. Flu B’s account for roughly a quarter of annual flu cases, many of which lead to hospitalization and death; they seem hardier than their A cousins against certain antiviral drugs. And scientists simply know a lot less about flu B’s: how, precisely, they interact with the immune system; what factors influence their sluggish evolutionary rate; the nuances of their person-to-person spread; their oddball animal-host range. And that lack of intel on what has for decades been a formidable infectious foe creates a risk all on its own.

    Flu lineages have dipped into relative obscurity before only to come roaring back. After the end of the H2N2 pandemic of the late 1950s, H1N1 appeared to flame out—only to reemerge nearly two decades later to greet a population full of young people whose immune systems hadn’t glimpsed it before. And as recently as the 1990s, the B lineage Victoria underwent a years-long ebb in most parts of the world, before ricocheting back to prominence in the early 2000s.

    As far as researchers can tell, Victoria is alive and well; during the globe’s most recent winter seasons, the lineage appears to have ignited late-arriving outbreaks in several countries, including in South Africa, Malaysia, and various parts of Europe. But based on the viral sequences that researchers have isolated from people sick with flu, Yamagata is still nowhere to be found, says Saverio Caini, a virologist at the cancer research center ISPRO, in Italy.

    The lineage was already teetering on a precipice before the pandemic began, van de Sandt told me. Yamagata and Victoria, which splintered apart in the early 1980s, are still closely related enough that they often compete for the same hosts. And just prior to 2020, Victoria, the more diverse and fleet-footed of the two B lineages, had been reliably edging out its cousin, pushing Yamagata’s prevalence down, down, down. That trend, coupled with several years of use of a well-matched Yamagata strain in the seasonal flu vaccine, meant that Yamagata “had already decreased in incidence and circulation,” van de Sandt said. With the odds so steeply stacked, the addition of pandemic mitigations may have been the final factor that snuffed the lineage out.

    Recently, a few countries—including China, Pakistan, and Belize—have tentatively reported possible Yamagata infections. But there’s been no conclusive genetic proof, several experts told me. Several parts of the world, including the United States, regularly use flu vaccines containing active flu viruses that can trip the same viral tests that the wild, disease-causing pathogens do. “So the reports could be contaminations,” van de Sandt said. Scientists would need to scour the virus’s genetic sequences to distinguish infection from injection; those data, however, haven’t emerged.

    Should the Yamagata dry spell continue, researchers may want to start considering snipping the lineage out of vaccines altogether, perhaps as early as the middle or end of this year. Doing so would punt the world back to the early 2010s, when flu shots were trivalent—designed to protect people against two A viruses, H3N2 and H1N1, plus either Victoria or Yamagata, depending on which lineage researchers forecasted would surge more. (They were often wrong.) Or maybe the space once used for Yamagata could feasibly be filled with another flavor of H3N2, the fastest mutator of the bunch.

    But purging Yamagata from the vaccine would be a gamble. If Yamagata is not gone for good, van de Sandt worries that booting it from the vaccine would leave the world vulnerable to a massive and deadly outbreak. Even Dhanasekaran, who is among the researchers who are fairly confident that we’ve seen the last of Yamagata, told me he doesn’t want to rule out the possibility that the virus is cloistering in an immunocompromised person with a chronic infection, and it’s unclear if it could reemerge from such a hiding place. The only thing scientists can do for now is be patient, says Jayna Raghwani, a computational biologist at the University of Oxford. “If we don’t see it in successive seasons for another two to three years, that will be more convincing,” she told me.

    If Yamagata’s death knell has actually rung, though, it will have reverberating effects. There’s no telling, for instance, how other flu lineages might be affected by their colleague’s supposed retirement. Perhaps Victoria, which can swap genetic material with Yamagata, will evolve more slowly without its partner. At the same time, Victoria may have an easier time infecting people now that it no longer needs to compete as often for hosts.

    If Yamagata has gone to pasture, “there won’t be a ceremony declaring the world Yamagata free,” Lauring told me. And it’s easy, he points out, to forget things we don’t see. But even if Yamagata seems gone for now, the effects of its demise will be significant enough that it can’t be forgotten—not just yet.

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    Katherine J. Wu

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  • Life Is Worse for Older People Now

    Life Is Worse for Older People Now

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    Last December, during a Christmas Eve celebration with my in-laws in California, I observed what I now realize was the future of COVID for older people. As everyone crowded around the bagna cauda, a hot dipping sauce shared like fondue, it was clear that we, as a family, had implicitly agreed that the pandemic was over. Our nonagenarian relatives were not taking any precautions, nor was anyone else taking precautions to protect them. Endive spear in hand, I squeezed myself in between my 94-year-old grandfather-in-law and his spry 99-year-old sister and dug into the dip.

    We all knew that older people bore the brunt of COVID, but the concerns seemed like a relic from earlier in the pandemic. The brutal biology of this disease meant that they disproportionately have fallen sick, been hospitalized, and died. Americans over 65 make up 17 percent of the U.S. population, but they have accounted for three-quarters of all COVID deaths. As the death count among older people began to rise in 2020, “a lot of my patients were really concerned that they were being exposed without anyone really caring about them,” Sharon Brangman, a geriatrician at SUNY Upstate University Hospital, told me.

    But even now, three years into the pandemic, older people are still in a precarious position. While many Americans can tune out COVID and easily fend off an infection when it strikes, older adults continue to face real threats from the illness in the minutiae of their daily life: grocery trips, family gatherings, birthday parties, coffee dates. That is true even with the protective power of several shots and the broader retreat of the virus. “There is substantial risk, even if you’ve gotten all the vaccines,” Bernard Black, a law professor at Northwestern University who studies health policy, told me. More than 300 people still die from COVID each day, and the overwhelming majority of them are older. People ages 65 and up are currently hospitalized at nearly 11 times the rate of adults under 50.

    Compounding this sickness are all the ways that, COVID aside, this pandemic has changed life for older adults. Enduring severe isolation and ongoing caregiver shortages, they have been disproportionately harmed by the past few years. Not all of them have experienced the pandemic in the same way. Americans of retirement age, 65 and older, are a huge population encompassing a range of incomes, health statuses, living situations, and racial backgrounds. Nevertheless, by virtue of their age alone, they live with a new reality: one in which life has become more dangerous—and in many ways worse—than it was before COVID.

    The pandemic was destined to come after older Americans. Their immune systems tend to be weaker, making it harder for them to fight off an infection, and they are more likely to have comorbidities, which further increases their risk of severe illness. The precarity that many of them already faced going into 2020—poverty, social isolation and loneliness, inadequate personal care—left them poorly equipped for the arrival of the novel coronavirus. More than 1 million people lived in nursing homes, many of which were densely packed and short on staff when COVID tore through them.

    A major reason older people are still at risk is that vaccines can’t entirely compensate for their immune systems. A study recently published in the journal Vaccines showed that for vaccinated adults ages 60 and over, the risk of dying from COVID versus other natural causes jumped from 11 percent to 34 percent within a year of completing their primary shot series. A booster dose brings the risk back down, but other research shows that it wears off too. A booster is a basic precaution, but “not one that everyone is taking,” Black, a co-author of the study, told me. Booster uptake among older Americans for the reengineered “bivalent” shots is the highest of all age groups, but still, nearly 60 percent have not gotten one.

    For every COVID death, many more older people develop serious illness. Risk increases with age, and people older than 70 “have a substantially higher rate of hospitalizations” than those ages 60 to 69, Caitlin Rivers, an epidemiologist at Johns Hopkins University, told me. Unlike younger people, most of whom fully recover from a bout with COVID, a return to baseline health is less guaranteed for older adults. In one study, 32 percent of adults over 65 were diagnosed with symptoms that lasted well beyond their COVID infection. Persistent coughs, aches, and joint pain can linger long after serious illness, together with indirect impacts such as loss of muscle strength and flexibility, which can affect older people’s ability to be independent, Rivers said. Older COVID survivors may also have a higher risk of cognitive decline. In some cases, these ailments could be part of long COVID, which may be more prevalent in older people.

    Certainly, some older adults are able to make a full recovery. Brangman said she has “old and frail” geriatric patients who bounced back after flu-like symptoms, and younger ones who still experience weakness and fatigue. Still, these are not promising odds. The antiviral Paxlovid was supposed to help blunt the wave of old people falling sick and ending up in the hospital—and it can reduce severe disease by 50 to 90 percent. But unfortunately, it is not widely used; as of July, just a third of Americans 80 or older took Paxlovid.

    The reality is that as long as the virus continues to be prevalent, older Americans will face these potential outcomes every time they leave their home. That doesn’t mean they will barricade themselves indoors, or that they even should. Still, “every decision that we make now is weighing that balance between risk and socialization,” Brangman said.

    Long before the pandemic, the threat of illness was already very real for older people.  Where America has landed is hardly a new way of life but rather one that is simply more onerous. “One way to think about it is that this is a new risk that’s out there” alongside other natural causes of death, such as diabetes and heart failure, Black said. But it’s a risk older Americans can’t ignore, especially as the country has dropped all COVID precautions. Since Christmas Eve, I have felt uneasy about how readily I normalized putting so little effort into protecting my nonagenarian loved ones, despite knowing what might happen if they got sick. For older people, who must contend with the peril of attending similar gatherings, “there’s sort of no good choice,” Black said. “The world has changed.”

    But this new post-pandemic reality also includes insidious effects on older people that aren’t directly related to COVID itself. Those who put off nonemergency visits to the doctor earlier in the pandemic, for example, risked worsening their existing health conditions. The first year of the pandemic plunged nearly everyone into isolation, but being alone created problems for older adults that still persist. Before the pandemic, the association between loneliness and higher mortality rates, increased cardiovascular risks, and dementia among older adults was already well established. Increased isolation during COVID amplified this association.

    The consequences of isolation were especially profound for older adults with physical limitations, Naoko Muramatsu, a community-health professor at the University of Illinois at Chicago, told me. When caregivers or family members were unable to visit, people who required assistance for even the smallest tasks, such as fetching the mail and getting dressed, had no options. “If you don’t walk around and if you don’t do anything, we can expect that cognitive function will decline,” Muramatsu said; she has observed this firsthand in her research. One Chinese American woman, interviewed in a survey of older adults living alone with cognitive impairment during the pandemic, described the debilitating effect of sitting at home all day.“I am so useless now,” she told the interviewer. “I am confused so often. I forget things.”

    Even older adults who have weathered the direct and indirect effects of the pandemic still face other challenges that COVID has exacerbated. Many have long relied on personal caregivers or the staff at nursing facilities. These workers, already scarce before the pandemic, are even more so now because many quit or were affected by COVID themselves. “Long-term care has been in a crisis situation for a long time, but it’s even worse now,” Muramatsu said, noting that many home care workers are older adults themselves. Nursing homes nationwide now have nearly 200,000 fewer employees compared with March 2020, which is especially concerning as the proportion of Americans over age 65 explodes.

    Older people won’t have one single approach to contending with this sad reality. “Everybody is trying to figure out what is the best way to function, to try to have some level of everyday life and activity, but also keep your risk of getting sick as low as possible,” Brangman said. Some of her patients are still opting to be cautious, while others consider this moment their “only chance to see grandchildren or concerts or go to family gatherings.” Either way, older Americans will have to wrestle with these decisions without so many of their peers who have died from COVID.

    Again, many of these people did not have it great before the pandemic, even if the rest of the country wasn’t paying attention. “We often don’t provide the basic social support that older people need,” Kenneth Covinsky, a clinician-researcher at the UCSF Division of Geriatrics, said. Rather, ageism, the willful ignorance or indifference to the needs of older people, is baked into American life. It is perhaps the main reason older adults were so badly affected by the pandemic in the first place, as illustrated by the delayed introduction of safety precautions in nursing homes and the blithe acceptance of COVID deaths among older adults. If Americans couldn’t bring themselves to care at any point over the past three years, will they ever?

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    Yasmin Tayag

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  • The COVID Question That Will Take Decades to Answer

    The COVID Question That Will Take Decades to Answer

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    To be a newborn in the year 2023—and, almost certainly, every year that follows—means emerging into a world where the coronavirus is ubiquitous. Babies might not meet the virus in the first week or month of life, but soon enough, SARS-CoV-2 will find them. “For anyone born into this world, it’s not going to take a lot of time for them to become infected,” maybe a year, maybe two, says Katia Koelle, a virologist and infectious-disease modeler at Emory University. Beyond a shadow of a doubt, this virus will be one of the very first serious pathogens that today’s infants—and all future infants—meet.

    Three years into the coronavirus pandemic, these babies are on the leading edge of a generational turnover that will define the rest of our relationship with SARS-CoV-2. They and their slightly older peers are slated to be the first humans who may still be alive when COVID-19 truly hits a new turning point: when almost everyone on Earth has acquired a degree of immunity to the virus as a very young child.

    Read: Is COVID a common cold yet?

    That future crossroads might not sound all that different from where the world is currently. With vaccines now common in most countries and the virus so transmissible, a significant majority of people have some degree of immunity. And in recent months, the world has begun to witness the consequences of that shift. The flux of COVID cases and hospitalizations in most countries seems to be stabilizing into a seasonal-ish sine wave; disease has gotten, on average, less severe, and long COVID seems to be somewhat less likely among those who have recently gotten shots. Even the virus’s evolution seems to be plodding, making minor tweaks to its genetic code, rather than major changes that require another Greek-letter name.

    But today’s status quo may be more of a layover than a final destination in our journey toward COVID’s final form. Against SARS-CoV-2, most little kids have fared reasonably well. And as more babies have been born into a SARS-CoV-2-ridden world, the average age of first exposure to this coronavirus has been steadily dropping—a trend that could continue to massage COVID-19 into a milder disease. Eventually, the expectation is that the illness will reach a stable nadir, at which point it may truly be “another common cold,” says Rustom Antia, an infectious-disease modeler at Emory.

    The full outcome of this living experiment, though, won’t be clear for decades—well after the billions of people who encountered the coronavirus for the first time in adulthood are long gone. The experiences that today’s youngest children have with the virus are only just beginning to shape what it will mean to have COVID throughout a lifetime, when we all coexist with it from birth to death as a matter of course.

    At the beginning of SARS-CoV-2’s global tear, the coronavirus was eager to infect all of us, and we had no immunity to rebuff its attempts. But vulnerability wasn’t just about immune defenses: Age, too, has turned out to be key to resilience. Much of the horror of the disease could be traced to having not only a large population that lacked protection against the virus—but a large adult population that lacked protection against the virus. Had the entire world been made up of grade-schoolers when the pandemic arrived, “I don’t think it would have been nearly as severe,” says Juliet Pulliam, an infectious-disease modeler at Stellenbosch University, in South Africa.

    Across several viral diseases—polio, chicken pox, mumps, SARS, measles, and more—getting sick as an adult is notably more dangerous than as a kid, a trend that’s typically exacerbated when people don’t have any vaccinations or infections to those pathogens in their rearview. The manageable infections that strike toddlers and grade-schoolers may turn serious when they first manifest at older ages, landing people in the hospital with pneumonia, brain swelling, even blindness, and eventually killing some. When scientists plot mortality data by age, many curves bend into “a pretty striking J shape,” says Dylan Morris, an infectious-disease modeler at UCLA.

    The reason for that age differential isn’t always clear. Some of kids’ resilience probably comes from having a young, spry body, far less likely to be burdened with chronic medical conditions that raise severe disease risk. But the quick-wittedness of the young immune system is also likely playing a role. Several studies have found that children are much better at marshaling hordes of interferon—an immune molecule that armors cells against viruses—and may harbor larger, more efficient cavalries of infected-cell-annihilating T cells. That performance peaks sometime around grade school or middle school, says Janet Chou, a pediatrician at Boston Children’s Hospital. After that, our molecular defenses begin a rapid tumble, growing progressively creakier, clumsier, sluggish, and likelier to launch misguided attacks against the tissues that house them. By the time we’re deep into adulthood, our immune systems are no longer sprightly, or terribly well calibrated. When we get sick, our bodies end up rife with inflammation. And our immune cells, weary and depleted, are far less unable to fight off the pathogens they once so easily trounced.

    Whatever the explanations, children are far less likely to experience serious symptoms, or to end up in the hospital or the ICU after being infected with SARS-CoV-2. Long COVID, too, seems to be less prevalent in younger cohorts, says Alexandra Yonts, a pediatrician at Children’s National Hospital. And although some children still develop MIS-C, a rare and dangerous inflammatory condition that can appear weeks after they catch the virus, the condition “seems to have dissipated” as the pandemic has worn on, says Betsy Herold, the chief of pediatric infectious disease at the Children’s Hospital at Montefiore, in the Bronx.

    Should those patterns hold, and as the age of first exposure continues to fall, COVID is likely to become less intense. The relative mildness of childhood encounters with the virus could mean that almost everyone’s first infection—which tends, on average, to be more severe than the ones that immediately follow—could rank low in intensity, setting a sort of ceiling for subsequent bouts. That might make concentrating first encounters “in the younger age group actually a good thing,” says Ruian Ke, an infectious-disease modeler at Los Alamos National Laboratory.

    COVID will likely remain capable of killing, hospitalizing, and chronically debilitating a subset of adults and kids alike. But the hope, experts told me, is that the proportion of individuals who face the worst outcomes will continue to drop. That may be what happened in the aftermath of the 1918 flu pandemic, Antia, of Emory, told me: That strain of the virus stuck around, but never caused the same devastation again. Some researchers suspect that something similar may have even played out with another human coronavirus, OC43: After sparking a devastating pandemic in the 19th century, it’s possible that the virus no longer managed to wreak much more havoc than a common cold in a population that had almost universally encountered it early in life.

    Such a fate for COVID, though, isn’t a guarantee. The virus’s propensity to linger in the body’s nooks and crannies, sometimes causing symptoms that last many months or years, could make it an outlier among its coronaviral kin, says Melody Zeng, an immunologist at Cornell University. And even if the disease is likely to get better than what it is now, that is not a very high bar to clear.

    Some small subset of the population will always be naive to the virus—and it’s not exactly a comfort that in the future, that cohort will almost exclusively be composed of our kids. Pediatric immune systems are robust, UCLA’s Morris told me. But “robust is not the same as infallible.” Since the start of the pandemic, more than 2,000 Americans under the age of 18 have died from COVID—a small fraction of total deaths, but enough to make the disease a leading cause of death for children in the U.S. MIS-C and long COVID may not be common, but their consequences are no less devastating for the children who experience them. Some risks are especially concentrated among our youngest kids, under the age 5, whose immune defenses are still revving up, making them more vulnerable than their slightly older peers. There’s especially little to safeguard newborns just under six months, who aren’t yet eligible for most vaccines—including COVID shots—and who are rapidly losing the antibody-based protection passed down from their mothers while they were in the womb.

    A younger average age of first infection will also probably increase the total number of exposures people have to SARS-CoV-2 in a typical lifetime—each instance carrying some risk of severe or chronic disease. Ke worries the cumulative toll that this repetition could exact: Studies have shown that each subsequent tussle with the virus has the potential to further erode the functioning or structural integrity of organs throughout the body, raising the chances of chronic damage. There’s no telling how many encounters might push an individual past a healthy tipping point.

    Racking up exposures also won’t always bode well for the later chapters of these children’s lives. Decades from now, nearly everyone will have banked plenty of encounters with SARS-CoV-2 by the time they reach advanced age, Chou, from Boston Children’s Hospital, told me. But the virus will also continue to change its appearance, and occasionally escape the immunity that some people built up as kids. Even absent those evasions, as their immune systems wither, many older people may not be able to leverage past experiences with the disease to much benefit. The American experience with influenza is telling. Despite a lifetime of infections and available vaccines, tens of thousands of people typically die annually of the disease in the United States alone, says Ofer Levy, the director of the Precision Vaccines Program at Boston Children’s Hospital. So even with the expected COVID softening, “I don’t think we’re going to reach a point where it’s, Oh well, tra-la-la,” Levy told me. And the protection that immunity offers can have caveats: Decades of research with influenza suggest that immune systems can get a bit hung up on the first versions of a virus that they see, biasing them against mounting strong attacks against other strains; SARS-CoV-2 now seems to be following that pattern. Depending on the coronavirus variants that kids encounter first, their responses and vulnerability to future bouts of illness may vary, says Scott Hensley, an immunologist at the University of Pennsylvania.

    Read: Are our immune systems stuck in 2020?

    Early vaccinations—that ideally target multiple versions of SARS-CoV-2—could make a big difference in reducing just about every bad outcome the virus threatens. Severe disease, long COVID, and transmission to other children and vulnerable adults all would likely be “reduced, prevented, and avoided,” Chou told me. But that’s only if very young kids are taking those shots, which, right now, isn’t at all the case. Nor are they necessarily getting protection passed down during gestation or early life from their mothers, because many adults are not up to date on COVID shots.

    Some of these issues could, in theory, end up moot. A hundred or so years from now, COVID could simply be another common cold, indistinguishable in practice from any other. But Morris points out that this reality, too, wouldn’t fully spare us. “When we bother to look at the burden of the other human coronaviruses, the ones who have been with us for ages? In the elderly, it’s real,” he told me. One study found that a nursing-home outbreak of OC43—the purported former pandemic coronavirus—carried an 8 percent fatality rate; another, caused by NL63, killed three out of the 20 people who caught it in a long-term-care facility in 2017. These and other “mild” respiratory viruses also continue to pose a threat to people of any age who are immunocompromised.

    SARS-CoV-2 doesn’t need to follow in those footsteps. It’s the only human coronavirus against which we have vaccines—which makes the true best-case scenario one in which it ends up even milder than a common cold, because we proactively protect against it. Disease would not need to be as inevitable; the vaccine, rather than the virus, could be the first bit of intel on the disease that kids receive. Tomorrow’s children probably won’t live in a COVID-free world. But they could at least be spared many of the burdens we’re carrying now.

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    Katherine J. Wu

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  • Airplane Toilets Could Catch the Next COVID Variant

    Airplane Toilets Could Catch the Next COVID Variant

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    Airplane bathrooms are not most people’s idea of a good time. They’re barely big enough to turn around in. Their doors stick, like they’re trying to trap you in place. That’s to say nothing of the smell. But to the CDC, those same bathrooms might be a data gold mine.

    This month, the agency has been speaking with Concentric, the public-health and biosecurity arm of the biotech company Ginkgo Bioworks, about screening airplane wastewater for COVID-19 at airports around the country. Although plane-wastewater testing had been in the works already (a pilot program at John F. Kennedy International Airport, in New York City, concluded last summer), concerns about a new variant arising in China after the end of its “zero COVID” policies acted as a “catalyst” for the project, Matt McKnight, Ginkgo’s general manager for biosecurity, told me. According to Ginkgo, even airport administrators are getting excited. “There have been a couple of airports who have actually reached out to the CDC to ask to be part of the program,” Laura Bronner, Ginkgo’s vice president of commercial strategies, told me.

    Airplane-wastewater testing is poised to revolutionize how we track the coronavirus’s continued mutations around the world, along with other common viruses such as flu and RSV—and public-health threats that scientists don’t even know about yet. Unlike sewer-wide surveillance, which shows us how diseases are spreading among large communities, airplane surveillance is precisely targeted to catch new variants entering the country from abroad. And unlike with PCR testing, passengers don’t have to individually opt in. (The results remain anonymous either way.) McKnight compares the technique to radar: Instead of responding to an attack after it’s unfolded, America can get advance warning about new threats before they cause problems. As we enter an era in which most people don’t center their lives on avoiding COVID-19, our best contribution to public health might be using a toilet at 30,000 feet.

    Fundamentally, wastewater testing on airplanes is a smaller-scale version of the surveillance that has been taking place at municipal water networks since early 2020: Researchers perform genetic testing on sewage samples to determine how much coronavirus is present, and which variants are included. But adapting the methodology to planes will require researchers to get creative. For one thing, airplane wastewater has a higher solid-to-liquid ratio. Municipal sewage draws from bathing, cooking, washing clothes, and other activities, whereas airplane sewage is “mainly coming from the toilet,” says Kata Farkas, a microbiologist at Bangor University. For a recent study tracking COVID-19 at U.K. airports, Farkas and her colleagues had to adjust their analytical methods, tweaking the chemicals and lab techniques used to isolate the coronavirus from plane sewage.

    Researchers also need to select flights carefully to make sure the data they gather are worth the effort of collecting them. To put it bluntly, not everyone poops on the plane—and if the total number of sampled passengers is very small, the analysis isn’t likely to return much useful data. “The number of conversations we’ve had about how to inconspicuously know how many people on a flight have gone into a lavatory is hysterical,” says Casandra Philipson, who leads the Concentric bioinformatics program. (Concentric later clarified that they do not have plans to actually monitor passengers’ bathroom use.) Researchers ended up settling on an easier metric: Longer flights tend to have more bathroom use and should therefore be the focus of wastewater testing. (Philipson and her colleagues also work with the CDC to test flights from countries where the government is particularly interested in identifying new variants.)

    Read: Are our immune systems stuck in 2020?

    Beyond those technical challenges, scientists face the daunting task of collaborating with airports and airlines—large companies that aren’t used to participating in public-health surveillance. “It is a tricky environment to work in,” says Jordan Schmidt, the director of product applications at LuminUltra, a Canadian biotech company that tests wastewater at Toronto Pearson Airport. Strict security and complex bureaucracies in air travel can make collecting samples from individual planes difficult, he told me. Instead, LuminUltra samples from airport terminals and from trucks that pull sewage out of multiple planes, so the company doesn’t need to get buy-in from airlines.

    Airplane surveillance seeks to track new variants, not individual passengers: Researchers are not contact-tracing exactly which person brought a particular virus strain into the country. For that reason, companies such as Concentric aren’t planning to alert passengers that COVID-19 was found on their flight, much as some of us might appreciate that warning. Testing airplane sewage can identify variants from around the world, but it won’t necessarily tell us about new surges in the city where those planes land.

    Airplane-wastewater testing offers several advantages for epidemiologists. In general, testing sewage is “dramatically cheaper” and “dramatically less invasive” than nose-swab testing each individual person in a town or on a plane, says Rob Knight, a medical engineering professor at UC San Diego who leads the university’s wastewater-surveillance program. Earlier this month, a landmark report from the National Academies of Sciences, Engineering, and Medicine (which Knight co-authored) highlighted international airports as ideal places to seek out new coronavirus variants and other pathogens. “You’re going to capture people who are traveling from other parts of the world where they might be bringing new variants,” Knight told me. And catching those new variants early is key to updating our vaccines and treatments to ensure that they continue to work well against COVID-19. Collecting more data from people traveling within the country could be useful too, Knight said, since variants can evolve at home as easily as abroad. (XBB.1.5, the latest variant dominating COVID-19 spread in the U.S., is thought to have originated in the American Northeast.) To this end, he told me, the CDC should consider monitoring large train stations or seaports too.

    Read: The COVID data that are actually useful now

    When wastewater testing first took off during the pandemic, the focus was mostly on municipal facilities, because they could provide data for an entire city or county at once. But scientists have since realized that a more specific view of our waste can be helpful, especially in settings that are crucial for informing public-health actions. For example, at NYC Health + Hospitals, the city’s public health-care system, wastewater data help administrators “see 10 to 14 days in advance if there are any upticks” in coronavirus, flu, or mpox, Leopolda Silvera, Health + Hospitals’ global-health deputy, told me. Administrators use the data in decisions about safety measures and where to send resources, Silvera said: If one hospital’s sewage indicates an upcoming spike in COVID-19 cases, additional staff can be added to its emergency department.

    Schools are another obvious target for small-scale wastewater testing. In San Diego, Rebecca Fielding-Miller directed a two-year surveillance program for elementary schools. It specifically focused on underserved communities, including refugees and low-income workers who were hesitant to seek out PCR testing. Regular wastewater testing picked up asymptomatic cases with high accuracy, providing school staff and parents with “up to the minute” information about COVID-19 spread in their buildings, Fielding-Miller told me. This school year, however, funding for the program ran out.

    Even neighborhood-level surveillance, while not as granular as sampling at a plane, hospital, or school, can provide more useful data than city-wide testing. In Boston, “we really wanted hyperlocal surveillance” to inform placements of the city’s vaccine clinics, testing sites, and other public-health services, says Kathryn Hall, the deputy commissioner at the city’s public-health agency. She and her colleagues identified 11 manhole covers that provide “good coverage” of specific neighborhoods and could be tested without too much disruption to traffic. When a testing site lights up with high COVID-19 numbers, Hall’s colleagues reach out to community organizations such as health centers and senior-living facilities. “We make sure they have access to boosters, they have access to PPE, they understand what’s going on,” Hall told me. In the nearby city of Revere, a similar program run by the company CIC Health showed an uptick in RSV in neighborhood wastewater before the virus started making headlines. CIC shared the news with day-care centers and helped them respond to the surge with educational information and PPE.

    Read: Whatever happened to toilet plumes?

    According to wastewater experts, hyperlocal programs can’t usher in a future of disease omnipotence all by themselves. Colleen Naughton, an environmental-engineering professor at UC Merced who runs the COVIDPoops19 dashboard, told me she would like to see communities with no wastewater surveillance get resources to set it up before more funding goes into testing individual buildings or manhole covers. The recent National Academies report presents a future of wastewater surveillance that includes both broad monitoring across the country and testing targeted to places where new health threats might emerge or where certain communities need local information to stay safe.

    This future will require sustained federal funding beyond the current COVID-19 emergency, which is set to expire if the Biden administration does not renew it in April. The United States needs “better and more technology, with a funding model that supports its development,” in order for wastewater’s true potential to be realized, Knight said. Airplane toilets may very well be the best first step toward that comprehensive sewage-surveillance future.

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    Betsy Ladyzhets

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  • It’s Beginning to Look a Lot Like Another COVID Surge

    It’s Beginning to Look a Lot Like Another COVID Surge

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    When I called the epidemiologist Denis Nash this week to discuss the country’s worsening COVID numbers, he was about to take a rapid test. “I came in on the subway to work this morning, and I got a text from home,” Nash, a professor at the City University of New York, told me. “My daughter tested positive for COVID.”

    Here we go again: For the first time in several months, another wave seems to be on the horizon in the United States. In the past two weeks, reported cases have increased by 53 percent, and hospitalizations have risen by 31 percent. Virus levels in wastewater, which can provide an advance warning of spread, are following a similar trajectory. After the past two years, a winter surge “was always expected,” Nash said. Respiratory illnesses thrive in colder weather, when people tend to spend more time indoors. Thanksgiving travel and gatherings were likewise predicted to drive cases, Anne Rimoin, an epidemiologist at UCLA, told me. If people were infected then, their illnesses will probably start showing up in the data around now. “We’re going to see a surge [that is] likely going to start really increasing in velocity,” she said.

    Winter has ushered in some of the pandemic’s worst moments. Last year, Omicron’s unwanted arrival led to a level of mass infection across the country that we had not previously seen. The good news this year is that the current rise will almost certainly not be as bad as last year’s. But beyond that, experts told me, we don’t know much about what will happen next. We could be in for any type of surge—big or small, long or short, national or regional. The only certain thing is that cases and hospitalizations are rising, and that’s not good.

    The pandemic numbers are ticking upward across the country, but so far the recent increases seem especially sharp in the South and West. The daily average of reported cases in Mississippi, Georgia, Texas, South Carolina, and Alabama has doubled in the past two weeks. Hospitalizations have been slower to rise, but over the same time frame, daily hospitalizations in California have jumped 57 percent and are now higher than anywhere else in the United States. Other areas of the country, such as New York City, have also seen troubling increases.

    Whether the nationwide spike constitutes the long-predicted winter wave, and not just an intermittent rise in cases, depends on whom you ask. “I think it will continue,” Gregory Poland, a professor of medicine at the Mayo Clinic, told me. “We will pour more gas on the fire with Christmas travel.” Others hesitated to classify the uptick as such, because it has just begun. “It’s hard to know, but the case numbers are moving in the wrong direction,” Rimoin said. Case counts are unreliable as people have turned to at-home testing (or just not testing at all), though hospitalizations and wastewater readings remain reliable, albeit imperfect, metrics. “I’ve not seen a big enough change to call it a wave,” Susan Kline, an infectious-diseases expert at the University of Minnesota Medical School, told me.

    But what to call the ongoing trend matters less than the fact that it exists. For now, what happens next is anyone’s guess. The dominant variants—the Omicron offshoots BQ.1 and BQ.1.1—are worrying, but they don’t pose the same challenges as what hit us last winter. Omicron drove that wave, taking us and our immune systems by surprise. The emergence of a completely new variant is possible this year—and would change everything—but that is considered unlikely.

    The lack of data on people’s immune status makes it especially difficult to predict the outcome of the current rise. Widespread vaccination and infection mean we have a stronger wall of immunity now compared with the previous two winters, but that protection inevitably fades with time. The problem is, people fall sick asynchronously and get boosted on their own schedules, so the timing varies for everyone. “We don’t know anything about how long ago people were [vaccinated], and we don’t know anything about hybrid immunity, so it’s impossible to predict” just how bad things could get, Nash said.

    Still, a confluence of factors has created the ideal conditions for a sustained surge with serious consequences for those who get sick. Fading immunity, frustratingly low booster uptake, and the near-total abandonment of COVID precautions create ideal conditions for the virus to spread. Meanwhile, treatments for those who do get very sick are dwindling. None of the FDA-approved monoclonal antibodies, which are especially useful for the immunocompromised, works against BQ.1 and BQ.1.1., which make up about 68 percent of cases nationwide. Paxlovid is still effective, but it’s underprescribed by providers and, by one medical director’s estimate, refused by 20 to 30 percent of patients.

    The upside is that few people who get COVID now will get very sick—fewer than in previous winters. Even if cases continue to surge, most infections will not lead to severe illness because the bulk of the population has some level of immunity from vaccination, previous infection, or both. Still, long COVID can be “devastating,” Poland said, and it can develop after mild or even asymptomatic cases. But any sort of wave would in all likelihood lead to an uptick in deaths, too. So far, the death rate has remained stable, but 90 percent of people dying now are 65 and older, and only a third of them have the latest booster. Such low uptake “just drives home the fact that we have not really done a good job of targeting the right people around the country,” Nash said.

    Even if the winter COVID wave is not ultimately a big one, it will likely be bad news for hospitals, which are already filling up with adults with flu and children with respiratory syncytial virus, or RSV. Many health-care facilities are swamped; the situation will only worsen if there is a big wave. If you need help for severe COVID—or any kind of medical issue—more than likely, “you’re not going to get the same level of care that you would have without these surges,” Poland said. Critically ill kids are routinely turned away from overflowing emergency rooms, my colleague Katherine J. Wu recently reported.

    We can do little to predict how the ongoing surge might develop other than simply wait. Soon we should have a better sense of whether this is a blip in the pandemic or something more serious, and the trends of winters past can be helpful, Kline said. Last year, the Omicron-fueled surge did not begin in earnest until mid-December. “We haven’t even gotten to January yet, so I really think we’re not going to know [how bad this surge will be] for two months,” Kline said. Until then, “we just have to stay put and watch.”

    It is maddening that, this far into the pandemic, “stay put and watch” seems to be the only option when cases start to rise. It is not, of course: Plenty of tools—masking, testing, boosters—are within our power to deploy to great effect. They could flatten the wave, if enough people use them. “We have the tools,” said Nash, whose rapid test came out negative, “but the collective will is not really there to do anything about it.”

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    Yasmin Tayag

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

    The Fatal Error of an Ancient, HIV-Like Virus

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    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.

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    Katherine J. Wu

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