Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context
Summary: 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-tro...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423003304 |
| _version_ | 1827861352226488320 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adrienne E. Swanstrom |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T13:36:37Z |
| format | Article |
| id | doaj.art-b06319c89f9342968fa2a346c4e69436 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-12T13:36:37Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-b06319c89f9342968fa2a346c4e694362023-08-24T04:35:16ZengElsevierEBioMedicine2352-39642023-09-0195104764Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in contextAdrienne E. Swanstrom0Robert J. Gorelick1Jorden L. Welker2Fabian Schmidt3Bing Lu4Kelly Wang5William Rowe6Matthew W. Breed7Kristin E. Killoran8Joshua A. Kramer9Duncan Donohue10James D. Roser11Paul D. Bieniasz12Theodora Hatziioannou13Cathi Pyle14James A. Thomas15Charles M. Trubey16Jim Zheng17Wade Blair18Stephen R. Yant19Jeffrey D. Lifson20Gregory Q. Del Prete21AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USALaboratory of Retrovirology, Rockefeller University, New York, NY, USAGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USADMS Applies Information Management Sciences, Frederick National Laboratory for Cancer Research, Frederick, MD, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USALaboratory of Retrovirology, Rockefeller University, New York, NY, USALaboratory of Retrovirology, Rockefeller University, New York, NY, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USAGilead Sciences, Foster City, CA, USA; Corresponding author. 333 Lakeside Drive, Foster City, CA 94404, USA.AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USAAIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Corresponding author. PO Box B, Frederick, MD 21702, USA.Summary: 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.http://www.sciencedirect.com/science/article/pii/S2352396423003304HIVPre-exposure prophylaxisPrEPNonhuman primateMacaqueCapsid |
| spellingShingle | 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 Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context EBioMedicine HIV Pre-exposure prophylaxis PrEP Nonhuman primate Macaque Capsid |
| title | Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context |
| title_full | Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context |
| title_fullStr | Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context |
| title_full_unstemmed | Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context |
| title_short | Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIVResearch in context |
| title_sort | long acting lenacapavir protects macaques against intravenous challenge with simian tropic hivresearch in context |
| topic | HIV Pre-exposure prophylaxis PrEP Nonhuman primate Macaque Capsid |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423003304 |
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