Key Points
- Research on HIV's conical capsid that began over 25 years ago led to the development of lenacapavir, the world's first capsid inhibitor.
- In June 2025, the FDA approved lenacapavir as a pre-exposure prophylactic (PrEP) to protect adults and adolescents from contracting HIV.
- Unlike daily oral PrEP, lenacapavir is administered twice a year. This feature, combined with its impressive efficacy in preventing HIV acquisition, make it a game-changer for slowing viral spread.
- The success of lenacapavir underscores the need to invest in basic science research today to support the generation of innovative drugs for the future.
HIV's genome is encapsulated in what looks like a wonky ice cream cone.
"The cone really captured our imagination. How does a protein make a cone?" mused Wesley Sundquist, Ph.D., Samuels Professor and Co-Chair of the Department of Biochemistry at the University of Utah, whose lab determined the organization of HIV's capsid proteins over 25 years ago. Since then, his team and others have shown that there is more to HIV's capsid than its peculiar shape.
For example, it facilitates reverse transcription of viral single-stranded (ssRNA) and protects the resulting DNA from host immune detection. It migrates into the host cell's nucleus-the site in which the viral genome enmeshes into the host chromosome-cracking open nuclear pores as it shuttles inside. Capsid is involved in later stages of infection, too, including viral particle maturation and assembly.
David Sanchez, Ph.D., a professor of biotechnology and pharmaceutical sciences in the College of Pharmacy at Western University of Health Sciences, likens HIV's replication process to a symphony. "Each part of the symphony has to be playing the right way for the music to happen. If you take away 1 piece or, you know, mess up their instrument, it's going to mess up the whole song."
Disrupting the song is exactly what antiretroviral therapies (ART) and pre-exposure prophylaxis (PrEP), a collection of drugs designed to control and prevent HIV infection, are meant to do. Most of these drugs mess with a few of HIV's instruments, namely reverse transcriptase and other enzymes needed for its replication. But the decadal focus on these validated drug targets means other members of the virus's orchestra, like capsid, have largely been left in the realm of basic science.
That is, until lenacapavir.
Capitalizing on Capsid
When Sundquist started his lab in the early 1990s, his focus on HIV's capsid was fueled by an interest in how proteins make large complexes. "But I do think we realized that we were working on an important biomedical problem," he said, noting that the scale of the HIV pandemic was becoming increasingly apparent.
Sundquist and his colleagues discovered that copies of HIV's capsid proteins, which arrange into flower-shaped hexamers and pentamers, slot next to each other at specific angles to make capsid's characteristic conical structure. Building on these findings, they showed that point mutations in HIV's capsid could severely impact its ability to infect cells and replicate-out of 48 mutations tested in their seminal 2003 study published in the Journal of Virology, over half led to a 20-100-fold decrease in viral infectivity.
"That [told us] that the virus really cared about its entire capsid protein, and if you perturbed it, the viral replication was much less efficient," Sundquist noted.
Did these results mean capsid had therapeutic potential? The consensus in the field had long been that capsid wasn't a great drug target. Researchers thought that you'd have to disrupt a good chunk of the 1,500 capsid proteins included in the structure to have any effect; other HIV proteins with fewer copies (e.g., integrase) were a less daunting target.
But the pharmaceutical company Gilead Sciences wasn't dissuaded. They took notice of what was coming out of the Sundquist Lab and, using those insights, embarked on a double-decade journey to create a revolutionary capsid-targeting drug.
The result is lenacapavir (Yeztugo), the world's first-ever HIV capsid inhibitor. The drug capitalizes on capsid's multi-partite role in viral replication. By inhibiting interactions between capsid proteins, lenacapavir impedes nuclear uptake of HIV, as well as the production of mature viral particles. Notably, the feature that scientists initially thought made capsid a bad target (i.e., its dynamic structure) is why the drug works. "If you bind a drug in 1 site, then it can perturb the structure of a hexamer 5 hexamers away. Because it's a lattice, everything's connected," Sundquist explained.
In June 2025, the FDA approved lenacapavir as a prophylactic to protect adults and adolescents from contracting HIV (the drug had been used since 2023 to treat patients with multi-drug-resistant HIV). The development is, by all accounts, a game-changer for slowing the spread of the virus.
Lenacapavir and the Future of HIV Prevention
Lenacapavir's high-key status can be attributed to several notable features. For one, thanks to a long half-life, the drug only needs to be administered via injection twice a year. Valeria D. Cantos, M.D., an associate professor in the Department of Medicine at Emory University, highlighted that widely used oral PrEP must be taken as prescribed to be effective (when taken as indicated, oral PrEP reduces the risk of sexual transmission of HIV by 99%).
However, "we know that, especially for people who are otherwise healthy, it can be hard to take medications every day to prevent an illness," she said. "People may have competing priorities in their lives. They may have limited access to getting their medication refilled, and as a result, the protective effect of oral [PrEP] is highly variable." Lenacapavir's sparse administration schedule reduces the burden, increasing chances of adherence among patients.
There's also the fact that the drug works extremely well. In a phase 3 trial in South Africa and Uganda that enrolled adolescent girls and young women, including pregnant women-populations heavily impacted by HIV but not often centered in studies-none of the over 2,100 participants who received lenacapavir acquired HIV. Compared to background HIV incidence, this translated to a 100% efficacy in preventing HIV acquisition. The drug was so effective, the double-blinded phase of the trial was stopped early, and lenacapavir was offered to all study participants.
Another phase 3 trial examining the safety and efficacy of the drug in cisgender men and gender-diverse individuals (groups that are highly vulnerable to acquiring HIV), produced similar results. "The study showed that lenacapavir is highly efficacious, with 96.9% efficacy compared to the background HIV incidence. Lenacapavir also demonstrated superiority to oral PrEP given as a combination of tenofovir disoproxil fumarate and emtricitabine," said Cantos, who was an author on the study.
"This just doesn't happen," Sanchez noted. "For HIV, we've never seen these numbers at this sustainable level."
Learning From Lenacapavir
The lenacapavir story offers several lessons and opportunities to carry into the fight against HIV. From a research perspective, it highlights the value in exploring HIV components and pathways that have largely been overshadowed by heavily exploited targets (e.g., reverse transcriptase).
"For a virus like HIV that mutates so much, we have to keep getting new tools in our kit to keep on attacking it. That's what this drug really shows us. We were able to find another drug target from [something] that we thought was not druggable. And I think that's the coolest thing," Sanchez said. "[It] gives me motivation to say 'it's okay to keep on looking for these other drug targets, because if we can find that extra one that makes these therapies even better, then we're a step forward.'"
If lenacapavir marks the beginning of a new era of groundbreaking HIV drugs, then it is increasingly vital to investigate not just how well they work, but also who benefits from them.
"Lenacapavir has been proven to be efficacious and safe. The next question is, how do we get it to the people who need it the most in the U.S. and worldwide?" Cantos said. "And that's a very difficult question to answer." The need for equitable distribution of life-saving medical interventions is not unique to lenacapavir. But steps have been taken during its development and rollout that set it apart.
For example, even before the drug was approved, Gilead Sciences applied for broad licensing agreements that facilitate manufacture and distribution of generic lenacapavir in more than 100 countries around the world with high incidences of HIV. Normally, drug approvals come first and licensing second; flipping the order of the steps means more people can potentially access the drug sooner.
Gaps remain, though. Cantos explained that most Latin American counties were not part of these agreements, despite an increasing HIV incidence in the region. "There's still a lot of work that needs to be done, [and] it will require continued commitment from all key players, including local governments, global funders, originating pharmaceutical companies…generic manufacturers and also community advocacy to assure that this medication is accessible worldwide," she said.
Preserving Basic Science Research
The ability to do that work comes with its own set of barriers. Recent funding cuts in the U.S. put the future of HIV research, prevention and treatment in a tenuous position. Funding for the U.S. President's Emergency Plan for AIDS Relief (PEPFAR)-credited with saving over 26 million lives and preventing millions of HIV infections over the past 20 years-was paused in early 2025. Swaths of research grants related to HIV have been canceled, including a $36 million grant to study HIV prevention methods worldwide.
"We're decreasing the possibility of finding that next big breakthrough," Sanchez said. "We're not making drugs out of thin air. Everything was basic biology first."
Sundquist agreed. "We don't know what we don't know, and so we can't reliably predict 1 project will work and another project won't. But I think what the integrated history teaches us is that, reliably, basic science gives new feedstocks for completely new kinds of innovative therapies."
Lenacapavir epitomizes that history. The seeds of the drug started from findings in Sundquist's lab decades ago; they grew and were built upon by other scientists bent on uncovering the ins and outs of HIV infection. As the fate of basic research in the U.S. remains uncertain, so does its ability to inform life-changing interventions.
"Sometimes we look at the benefit that's right in front of us, and we say, 'we're only going to support these things that are giving us the benefit right now, or tomorrow or the next day,'" Sanchez highlighted. "But then you look at lenacapavir, [it took] decades of research, and now we have this outcome. We have to be mindful not to just focus on things that are giving us immediate payback."
