HMN 2026: How HIV resistance to lenacapavir weakens the virus’s ability to replicate

Lenacapavir (LEN) is an antiviral medication used to treat and prevent HIV/AIDS and was first approved for individuals with drug-resistant infections in 2022. While there is still no vaccine for the virus, the twice-yearly injectable is “the next best thing,” according to the World Health Organization. However, even before the drug was approved, it was known that the virus could develop resistance to it, though this was rare. But now, a new study published in the journal Science Translational Medicine has shown that this resistance comes at a cost to the virus’s ability to survive and replicate.

Lenacapavir works by disrupting the HIV-1 capsid (the protective shell that encases the viral RNA), preventing the virus from protecting its genetic material or making copies of itself.

M66I mutation

To understand what was happening at the molecular level as individuals developed resistance to LEN, researchers analyzed virus samples from patients enrolled in two major clinical trials. They identified a group of mutations in the virus shell, such as Q67H and T107A, that helped the virus survive the drug. The most common and powerful mutation they discovered is called M66I.

Using advanced computer modeling, the team discovered how these mutations work. LEN usually binds tightly to a specific pocket on the HIV capsid, but M66I alters the pocket’s shape so LEN no longer fits, or disrupts the hydrogen bonds that keep the drug in place. This reduces the drug’s effectiveness by over 2,500-fold in some cases.

The cost of resistance

But this comes at a cost to the virus. According to the study, the ability of these drug-resistant viruses to replicate and spread can drop to as low as 13% of a normal virus. The scientists also found that when a single mutation makes a virus weak, sometimes it develops subsequent mutations that may improve its replication speed. However, even these new versions of the virus are not as strong as the original.

Ultimately, of course, the research is good news. The fact that the resistant versions of the virus are weakened demonstrates that the drug is working. It also illustrates the benefits of combining LEN with other HIV medications. If the virus evades one, the others can finish it off.

“In most cases, LEN resistance coincided with substantial replication capacity defects,” commented the study authors in their paper. “Together, these data support the development of treatment regimens that combine LEN with other active antiretrovirals to maintain durable suppression.”

The findings will also be useful to scientists designing the next generation of LEN medications so they can fit the capsid pocket even better and stay locked in place.

A Focus article on the research was also published in Science Translational Medicine.

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