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When HIV pays the price: Fitness costs behind lenacapavir resistance

Manish C Choudhary1, Jonathan Z Li1

  • 1Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Science Translational Medicine
|January 7, 2026
PubMed

Insights

Human immunodeficiency virus (HIV) develops resistance to lenacapavir through various mutation routes. These pathways result in different resistance and fitness characteristics, impacting treatment efficacy.

Area of Science:

  • Virology
  • Drug Resistance Studies
  • Molecular Biology

Background:

  • Lenacapavir is a novel long-acting HIV-1 capsid inhibitor.
  • Understanding HIV-1 resistance mechanisms is crucial for effective treatment strategies.

Purpose of the Study:

  • To investigate the diverse mutational pathways HIV-1 utilizes to develop resistance to lenacapavir.
  • To characterize the resistance and fitness profiles associated with distinct lenacapavir resistance mutations.

Main Methods:

  • The study likely involved analyzing HIV-1 sequences from patients or experimental evolution studies.
  • Resistance profiling was assessed through phenotypic or genotypic assays.
  • Fitness was evaluated by measuring viral replication rates.

Main Results:

  • Multiple distinct mutational pathways conferring lenacapavir resistance were identified.
  • Specific mutations exhibited varying degrees of resistance and impact on viral fitness.
  • The interplay between different mutations and their effect on resistance was elucidated.

Conclusions:

  • HIV-1 can evolve resistance to lenacapavir through several independent genetic routes.
  • The identified pathways and their associated profiles provide insights into potential treatment challenges.
  • This research highlights the adaptability of HIV-1 in response to novel antiviral agents.

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