| |
Lenacapavir treatment-emergent HIV-1 capsid resistance mutations are frequently associated with replication defects
|
| |
| |
Download the PDF here
Download the PDF here
Science Translational Medicine
7 Jan 2026
2 pdfs attached
Abstract
Lenacapavir (LEN) is a long-acting HIV-1 capsid inhibitor that binds to the HIV-1 capsid protein with picomolar antiviral activity, disrupting its function and inhibiting viral replication. Here, we identified capsid mutations in samples from individuals treated with LEN across two clinical trials that were considered potential LEN resistance-associated mutations. The gag encoding regions of clinical isolates with capsid mutations, as well as associated site-directed mutants, were cloned into the infectious molecular clone pXXLAI and pNL4-3-JRFL-secNLuc, encoding replication-competent HIV-1. Their effects on LEN susceptibility, replication kinetics, and three-dimensional capsid structure were investigated. Phenotypic analyses of the HIV-1 clinical isolates and site-directed mutants revealed that all resistance-associated mutations decreased LEN susceptibility to various degrees but were frequently associated with substantial replication defects. Structural modeling confirmed that LEN binding in the binding pocket was altered in the presence of capsid mutations, with predicted binding affinity changes correlating with observed potency shifts. These findings provide insights into LEN-resistance mechanisms and underscore the unusually high fitness costs associated with treatment-emergent capsid mutations.
----------------------
editorial
When HIV pays the price: Fitness costs behind lenacapavir resistance
7 Jan 2026
pdf attached
MOVING FORWARD
What might these findings mean for the use of LEN? First, it is interesting to note that the various LEN trials reported different resistance mutation pathways. The CAPELLA study illustrates how inadequate viral suppression (e.g., in the setting of functional monotherapy with LEN) in those with prior multidrug HIV resistance can drive the selection of high-level LEN resistance, especially that of M66I (5, 8). Although M66I imposes severe fitness costs, it readily emerged in the setting of limited companion antiretroviral drug activity, where any virus that partially evades LEN can gain a decisive selective advantage. In contrast, LEN resistance followed a different pattern (Q67H and K70R) in the CALIBRATE trial of ART-naïve participants, which was consistent with selection for mutations that conferred intermediate resistance but with higher replication capacity (9). Last, in PURPOSE 2, the two LEN PrEP breakthrough infections both harbored the N74D mutation (4, 9). Although preliminary, these results suggest the intriguing possibility that the most likely LEN resistance mutations that emerge may depend on the treatment context.
|
|
| |
| |
|
|
|
