An HIV Genome from Two Decades Before Its Discovery
An HIV Genome From Two Decades Before Its Discovery
In 1966, a 38-year-old man visited a hospital in what is now the Democratic Republic of Congo. His name, his symptoms, and everything about him beyond his age and gender have been lost to history. But a piece of one of his lymph nodes was collected and preserved. By analyzing it, a team of researchers led by Michael Worobey from the University of Arizona have shown that the man was infected by HIV, the virus that causes AIDS. He wouldn’t have known it, though, and nor would his doctors. HIV was formally discovered 17 years later.By wresting tiny genetic fragments from that tissue sample, Worobey’s team has almost completely reconstructed HIV’s genome from a time before anyone even knew it existed. And that work helps to flesh out the origin story of what would become one of the most important pandemics in human history. “There’s no other way to test these important inferences about the origins of one of the most important infectious diseases to ever hit humans,” says Worobey, who spent about five years trying to piece together that one tiny genome. “In retrospect, we’d probably do it again, but it’s crazy how much work it was.”HIV was identified only in the 1980s, after a mysterious new syndrome began affecting men in United States. It seemed to come out of nowhere, but it had actually originated decades earlier and a continent away. We know this because as the virus spreads, its genes change. By comparing those changes and estimating how quickly they happen, scientists can backtrack their way through HIV’s evolutionary history to its very beginning.The place, most likely: southern Cameroon. The estimated time: the 1920s. There and then, a chimpanzee virus hopped into some unlucky person, before making its way to the city now known as Kinshasa. In a populous and growing hub with a multitude of hosts, the new virus gained ground, eventually spawning lineages that spread around the world.Read: Stopping HIV would require an entirely different TrumpThis long history means that many people must have been infected with HIV before anyone knew what was making them sick. Samples of their tissues were collected by pathologists, treated with a chemical fixative, embedded in wax, examined under microscopes (likely to no avail), and then stored in drawers. That process (and especially the fixative) does horrible things to the RNA molecules that comprise HIV’s genome, “but not horrible enough to destroy them completely,” Worobey told me. “It turns out that you can retrieve [RNA] more than 50 years later, even if the thing has been sitting in a drawer at ambient temperature. Which can be pretty warm in Kinshasa.”But since HIV hadn’t even been identified, there’s no easy way of telling which old sample might contain traces of the virus. Finding those traces is like looking for a largely corroded needle in a thousand haystacks. Understandably, then, despite two decades of searching, scientists have only twice found traces of HIV from its prediscovery period in Kinshasa. David Ho from Rockefeller University found one in a blood sample from 1959; Worobey identified another in a lymph node from 1960.Read: How one man was wrongly blamed for bringing AIDS to AmericaIn both cases, barely anything of the virus’s RNA remained—just 1 percent of the total. Those pieces were enough to prove that HIV was circulating in Kinshasa decades before its discovery, and to sketch the outlines of the virus’s history. But since fragmentary evidence can be misleading, Worobey wanted to get a complete historical genome.His colleagues Sophie Gryseels and Tom Watts developed more sensitive tools for extracting RNA and applied them to more than 1,600 tissue samples from the University of Kinshasa. They found just one with traces of HIV and spent five years pulling every piece of RNA they could from it. “There are very sophisticated evolutionary models you can use to trace back what has happened through history, but they’re still models,” Gryseels told me. “With old genetic material, you can see what reality was actually like.”The old virus most closely resembled those from subtype C—the most prevalent lineage of HIV, and one that dominates in southern Africa today. But the 1966 virus wasn’t actually part of that group. It was more of a distant cousin, and it suggests that what we see of HIV today is just a small fraction of the total diversity that existed in Kinshasa in the 1960s. Only a few of those historical viruses then broke out, to become global problems.“Why are we interested in fossils? Because they tell a story,” says Beatrice Hahn, from the Perelman School of Medicine, who studies the evolution of HIV. “This HIV ‘fossil’ is no different. It’s an important piece in the evolutionary puzzle.”Read: A mutation that resists HIV has other harmful consequencesThe team also used the 1966 sample to check the history of HIV that they and others had gleaned by looking at modern viruses. Happily, that narrative turns out to be mostly right. The team estimates that the virus first arose sometime between 1896 and 1905—a little earlier than what others have calculated, but within the right ballpark. HIV’s present, it seems, is a good indicator of its past.That’s not always the case with viruses. When researchers found traces of hepatitis B from the Bronze Age, they learned that the virus evolved 100 times more slowly than anyone had thought, which radically revised estimates of its origins. Even SIV, HIV’s chimp-infecting cousin, evolved at different rates in the distant past and in recent history, making it hard to work out when it arose. HIV, by contrast, has been more consistent. “It’s very reassuring,” Worobey said.It might seem unexciting to spend a lot of time to learn that everything you knew was more or less right, but science depends upon such work. Without it, entire edifices of research can be constructed on shaky or nonexistent foundations.The study is “admirable,” says Bette Korber from Los Alamos National Laboratory, and “the reconstruction of HIV’s emergence and spread is very important.” Korber pioneered such reconstructions: She created the first decent estimate of HIV’s date of origin, using a genetic database that she and others (including Worobey’s team) have repeatedly turned to. She notes that 60 million to 100 million people have been infected with HIV, and 25 million to 50 million have died—a scale of suffering comparable to past world wars. “HIV has left a wound of deepest sorrow across humanity,” she says. “It is part of the human experience. We need to understand it.”That wouldn’t be possible, Worobey added, without the work of the Congolese pathologists who collected the relevant tissue samples decades ago. Their names are unknown too, and even their modern-day counterparts can go unnoticed. “They’re often unappreciated,” Worobey said. “They not only help the doctors you interact with directly but also play a crucial role in preserving these collections of tissues, which are now helping us to figure out the true history of this important virus.”