Building the blueprint to block HIV

Every year, more than one million people contract HIV. Preventive drugs known as preexposure prophylaxis, or PrEP, can block infection, but only when taken daily. That is unrealistic in many parts of the world where access to pills is unreliable and where stigma adds another barrier. Scientists have sought a simpler, longer-lasting option.

Dave Titensor

Wesley Sundquist draws a diagram of HIV.

At the University of Utah, Wesley Sundquist’s three decades of work deciphering the structure and function of the HIV capsid helped make that goal a reality. His discoveries laid the groundwork for Lenacapavir, a new injectable PrEP that can protect against infection for six months at a time.

Sundquist showed that the capsid was critical to HIV infection. It protects the viral genome, facilitates reverse transcription and helps the virus enter the nucleus. His work also revealed that the capsid is cone shaped and built from hexamers and pentamers, with regions that are particularly sensitive to disruption. These two findings, that the capsid is both essential and vulnerable, make it a promising drug target.

“Even small changes like drug binding would be detrimental to the virus,” Sundquist said. “We (originally) thought of the capsid as being more solid and a less important object than it's turned out to be.”

When Gilead’s Tomas Cihlar saw Sundquist’s work, he reached out with a question that would change HIV prevention: Could this shell be a key to preventing infection? Sundquist immediately said yes and set a collaboration in motion.

They were correct. Gilead went on to develop Lenacapavir, based on the capsid biology provided by Sundquist and colleagues. The drug deforms the capsid and makes it fragile. A fragile capsid cannot perform its functions, so the virus cannot infect new cells.

Janet Iwasa

A 3D rendering of HIV showing the outer shell, or capsid (yellow and purple), enveloping the viral RNA genome (blue).

Trials of Lenacapavir were first carried out in high-risk regions of South Africa in cisgender women. No one received a placebo. Instead, the comparison was between different forms of PrEP: daily pills or Lenacapavir injections. The women receiving Lenacapavir had no new infections during the study, while those taking the pills had infection rates similar to the current rates in the area, largely because many did not take the pills regularly.

“That amounted to 100 percent efficacy,” Linda-Gail Bekker, director of the Desmond Tutu HIV Centre at the University of Cape Town, said in an interview with Science. “And I have never seen a result like that.”

The trial was repeated in men and a gender diverse population with similarly strong results.

Image credit: Owen Pornillos, Ph.D.; Barbie Ganser, Ph.D.

Cryogenic electron microscopy (left) and molecular modeling (right) allowed Wesley Sundquist to study the viral capsid.

For the first time, researchers saw what true prevention could look like: protection that required almost no effort from the user and approached the level a fully effective vaccine might provide.

Sundquist and Cihlar were named to Time’s list of 100 most influential people of 2025, and Lenacapavir was named American Association for the Advancement of Science’s Breakthrough of the Year Award in 2025.

Sundquist will speak about the HIV capsid and its role in Lenacapavir during his keynote address at the American Society for Biochemistry and Molecular Biology’s 2026 annual meeting.