Within each person living with HIV, viral evolution unfolds at a remarkable pace. As the virus replicates, it rapidly accumulates mutations, generating thousands of genetically distinct viral variants. That extraordinary diversity has long complicated efforts to vaccinate against and cure HIV.
Despite HIV’s immense diversity, some antibodies can recognize and neutralize a broad range of viral variants. These broadly neutralizing antibodies (bNAbs) have emerged as promising tools for both HIV treatment and prevention. But even bNAbs can eventually be outpaced by HIV’s rapid evolution. Mutations can subtly reshape the virus, allowing HIV to escape recognition by bNAbs while retaining its ability to infect cells.
Scientists have long known that HIV can become resistant to antibody therapies. What has been harder to track is exactly how that escape unfolds.
Researchers from Dr. Lillian Cohn's lab in the Vaccine and Infectious Disease Division and Dr. Alison Feder’s lab at the University of Washington set out to map HIV’s escape routes. Doing so meant confronting the sheer diversity of HIV variants circulating within each person. Fred Hutch senior staff scientist Elena Giorgi put the scale of that complexity into perspective: “The amount of viral diversity found across one season of influenza viruses worldwide can be found within the HIV population of a single person.” Each of those viral variants represents a potentially different starting point from which HIV can evolve.
Mapping those escape routes could reveal whether HIV follows recurring evolutionary patterns, offering clues for how researchers might stay one step ahead of the virus.
In recent work led by Elena Romero, a former graduate student in the Feder lab, and Abigail Clyde, a former technician in the Cohn lab, the team tracked that evolutionary escape with unprecedented detail. They examined longitudinal samples from clinical trials in which people living with HIV received one of two broadly neutralizing antibodies in clinical development, 10-1074 and 3BNC117.
The team used long-read, deep sequencing to recover nearly 7000 full-length sequences of the HIV env gene, which encodes the viral envelope targeted by the antibodies. The approach provided 3.5 to 7.5 times greater sequencing depth than earlier studies, making it easier to detect rare viral variants that might otherwise be missed. And because the researchers sequenced the full env gene rather than short fragments, they could see resistance mutations in the broader genetic backgrounds in which they arose.
Together, that depth and length gave the researchers a much richer view of HIV evolution over time. They could distinguish individual viral lineages and watch as they emerged, disappeared, or expanded. By following those lineages, the researchers found that the routes HIV took depended on both the antibody it encountered and the virus’s genetic starting point.
They were also able to see how often HIV arrived at similar evolutionary solutions. Evolutionary biologists call this parallel evolution: the independent emergence of similar adaptations under the same selective pressure.
That pattern was especially striking in people treated with 10-1074. Across participants, and among distinct viral lineages within the same person, HIV repeatedly acquired escape mutations at the same few sites near the antibody’s target.
Escape from 3BNC117 followed a less consistent path. The mutations that emerged depended more strongly on the genetic makeup of each person’s starting viral population, underscoring that the route HIV takes around one antibody may look very different from the route it takes around another.
Rather than searching for a single antibody HIV cannot escape, researchers may be able to use knowledge of the virus's available escape routes to choose combinations that close off several paths at once. As Cohn put it, "Our ultimate goal is finding combinations of antibodies that don't fail and understanding how HIV evolves escape routes is the first step toward that goal”.
By revealing the paths HIV takes to escape individual antibodies and how often evolution discovers the same paths independently, the study could help researchers design combinations that make HIV's next escape route harder to find.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Alison F. Feder contributed to this research.
The spotlighted research was supported by the National Institutes for Health, the Pew Charitable Trusts Research Scholars Program, the Gilead Sciences Research Scholars Program in HIV, and the Genomics and Bioinformatics Shared Resource of the Fred Hutchinson Cancer Center/University of Washington/Seattle Children’s Cancer Consortium funded by the National Cancer Institute.
Romero EV, Clyde AE, Giorgi EE, Westfall DH, Azam W, Taylor ML, Caskey M, Feder AF, and Cohn LB. 2026. Recurrent mutations drive rapid HIV escape from two broadly neutralizing antibodies in vivo. PNAS. DOI: 10.1073/pnas.2524021123.
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.