HIV Resistance to Lenacapavir: A Costly Evolution for the Virus | Medical Xpress

The landscape of HIV treatment and prevention continues to evolve with long-acting antiretroviral therapies offering latest hope for those living with, or at risk of contracting, the virus. However, as with all antiviral medications, the potential for drug resistance looms. Recent research published in Science Translational Medicine sheds light on the development of resistance to lenacapavir, a groundbreaking HIV capsid inhibitor, and importantly, reveals that this resistance often comes at a significant cost to the virus itself.

Lenacapavir, approved in both the United States and Europe, represents a major step forward in HIV management. The drug, initially hailed as Science magazine’s “Breakthrough of the Year” in 2024, distinguishes itself not only through its infrequent dosing schedule – just two injections annually – but also through its unique mechanism of action. Unlike many previous HIV medications that target viral enzymes, lenacapavir directly interferes with the viral capsid, the protective shell surrounding HIV’s genetic material. This novel approach has proven highly effective, particularly for individuals with multidrug-resistant HIV-1.

The Cost of Resistance

Researchers, led by Dr. Nina Pennetzdorfer at Gilead Sciences, meticulously investigated how HIV adapts to lenacapavir. Their study, detailed in Science Translational Medicine, demonstrated that while HIV can indeed develop mutations that confer resistance to the drug, these mutations frequently impair the virus’s ability to replicate efficiently. The virus trades the ability to evade the drug for a diminished capacity to spread and infect.

The team analyzed 84 capsid mutants, both those observed in clinical trials and those engineered in the lab through a process called site-directed mutagenesis. They discovered that certain mutations altered the structure of the capsid, reducing lenacapavir’s ability to bind. However, the most resistant viral variants also exhibited the poorest replication rates, suggesting that these strains would struggle to compete with non-resistant viruses in the absence of the drug.

This finding is particularly encouraging, as it suggests that the emergence of lenacapavir resistance may not necessarily translate into widespread treatment failure. The “fitness cost” associated with resistance could limit the spread of resistant strains, preserving the drug’s effectiveness for a longer period.

Understanding Resistance Pathways

The study identified three primary pathways through which HIV develops resistance to lenacapavir. The first, centered around the M66I mutation, was the most prominent pathway observed in individuals with heavily treatment-experienced HIV-1 during the CAPELLA clinical trial. The second involved mutations Q67H and K70H/R, commonly seen in the CALIBRATE trial. A third pathway encompassed other resistance-associated mutations that conferred lower to medium levels of resistance.

As Drs. Manish Choudhary and Jonathan Li of Harvard Medical School and Brigham and Women’s Hospital pointed out in an accompanying commentary, identifying these resistance pathways is crucial for guiding future drug development and treatment strategies.

Implications for Treatment and Prevention

The development of lenacapavir, a process spanning two decades at Gilead Sciences, represents a significant departure from traditional HIV antiviral approaches. The drug’s unique target – the capsid – offers a new avenue for combating the virus. The HIV capsid is a complex structure, described as a fullerene cone, that protects the viral genome during infection. Disrupting this structure hinders the virus’s ability to infect new cells and evade the immune system.

The findings from Pennetzdorfer’s research have important implications for both HIV treatment and pre-exposure prophylaxis (PrEP). As lenacapavir gains wider apply in both contexts, maintaining fully active companion drugs during treatment becomes paramount. This ensures that even if resistance to lenacapavir emerges, other medications can continue to suppress the virus. Improved access to resistance testing and surveillance is essential for monitoring the emergence and spread of resistant strains.

The study also underscores the need for continued investment in the development of next-generation capsid inhibitors. By understanding the mechanisms of resistance and the associated fitness costs, researchers can design new drugs that are less susceptible to resistance and maintain their effectiveness over time.

What Comes Next

The insights gained from this research will inform ongoing efforts to optimize lenacapavir-based treatment regimens and PrEP strategies. Researchers will continue to monitor for the emergence of resistance mutations and assess their impact on viral fitness. Further studies are planned to investigate the potential for combining lenacapavir with other novel antiviral agents to further reduce the risk of resistance. Public health agencies will also refine surveillance programs to track the prevalence of resistant strains and inform clinical guidelines.

the goal is to ensure that lenacapavir remains a valuable tool in the fight against HIV, providing long-term protection for individuals at risk and improving the lives of those living with the virus. The ongoing research and vigilance will be critical to achieving this goal.

Written for you by our author Delthia Ricks, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You’ll get an ad-free account as a thank-you.

Nina Pennetzdorfer et al, Lenacapavir treatment–emergent HIV-1 capsid resistance mutations are frequently associated with replication defects, Science Translational Medicine (2026). DOI: 10.1126/scitranslmed.aea0947

Manish C. Choudhary et al, When HIV pays the price: Fitness costs behind lenacapavir resistance, Science Translational Medicine (2026). DOI: 10.1126/scitranslmed.aed6475

Journal information: Science Translational Medicine