Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV

Adrienne E. Swanstrom, Robert J. Gorelick, Jorden L. Welker, Fabian Schmidt, Bing Lu, Kelly Wang, William Rowe, Matthew W. Breed, Kristin E. Killoran, Joshua A. Kramer, Duncan Donohue, James D. Roser, Paul D. Bieniasz, Theodora Hatziioannou, Cathi Pyle, James A. Thomas, Charles M. Trubey, Jim Zheng, Wade Blair, Stephen R. Yant*Jeffrey D. Lifson, Gregory Q. Del Prete*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Long-acting subcutaneous lenacapavir (LEN), a first-in-class HIV capsid inhibitor approved by the US FDA for the treatment of multidrug-resistant HIV-1 with twice yearly dosing, is under investigation for HIV-1 pre-exposure prophylaxis (PrEP). We previously derived a simian-tropic HIV-1 clone (stHIV-A19) that encodes an HIV-1 capsid and replicates to high titres in pigtail macaques (PTM), resulting in a nonhuman primate model well-suited for evaluating LEN PrEP in vivo. Methods: Lenacapavir potency against stHIV-A19 in PTM peripheral blood mononuclear cells in vitro was determined and subcutaneous LEN pharmacokinetics were evaluated in naïve PTMs in vivo. To evaluate the protective efficacy of LEN PrEP, naïve PTMs received either a single subcutaneous injection of LEN (25 mg/kg, N = 3) or vehicle (N = 4) 30 days before a high-dose intravenous challenge with stHIV-A19, or 7 daily subcutaneous injections of a 3-drug control PrEP regimen starting 3 days before stHIV-A19 challenge (N = 3). Findings: In vitro, LEN showed potent antiviral activity against stHIV-A19, comparable to its potency against HIV-1. In vivo, subcutaneous LEN displayed sustained plasma drug exposures in PTMs. Following stHIV-A19 challenge, while all vehicle control animals became productively infected, all LEN and 3-drug control PrEP animals were protected from infection. Interpretation: These findings highlight the utility of the stHIV-A19/PTM model and support the clinical development of long-acting LEN for PrEP in humans. Funding: Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab; federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I; NIH grant R01AI078788.

Original languageEnglish (US)
Article number104764
StatePublished - Sep 2023


  • Capsid
  • HIV
  • Macaque
  • Nonhuman primate
  • Pre-exposure prophylaxis
  • PrEP

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


Dive into the research topics of 'Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV'. Together they form a unique fingerprint.

Cite this