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

doi:10.1016/j.ebiom.2023.104764

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

Bioengineering

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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 language	English (US)
Article number	104764
Journal	EBioMedicine
Volume	95
DOIs	https://doi.org/10.1016/j.ebiom.2023.104764
State	Published - Sep 2023

Bibliographical note

Funding Information:
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.The authors thank George Muthua and the animal care staff of the Laboratory Animal Sciences Program, Frederick National Laboratory, for expert animal care and support. The authors also thank Brandon Keele for assistance generating viral CA amino acid sequence alignments and Pamela Beltowski for assistance with figure production. The anti-CD8 alpha [MT807R1] antibody used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116). This study was funded in part from Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab, in part by NIH grant R01AI078788 (to TH), and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Funding Information:
The authors thank George Muthua and the animal care staff of the Laboratory Animal Sciences Program, Frederick National Laboratory, for expert animal care and support. The authors also thank Brandon Keele for assistance generating viral CA amino acid sequence alignments and Pamela Beltowski for assistance with figure production. The anti-CD8 alpha [MT807R1] antibody used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116). This study was funded in part from Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab , in part by NIH grant R01AI078788 (to TH), and in part with federal funds from the National Cancer Institute , National Institutes of Health , under Contract No. 75N91019D00024 / HHSN261201500003I . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Publisher Copyright:
© 2023 The Author(s)

Keywords

Capsid
HIV
Macaque
Nonhuman primate
Pre-exposure prophylaxis
PrEP

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2023.104764

Cite this

Swanstrom, A. E., Gorelick, R. J., Welker, J. L., Schmidt, F., Lu, B., Wang, K., Rowe, W., Breed, M. W., Killoran, K. E., Kramer, J. A., Donohue, D., Roser, J. D., Bieniasz, P. D., Hatziioannou, T., Pyle, C., Thomas, J. A., Trubey, C. M., Zheng, J., Blair, W., ... Del Prete, G. Q. (2023). Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV. EBioMedicine, 95, Article 104764. https://doi.org/10.1016/j.ebiom.2023.104764

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title = "Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV",

abstract = "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 na{\"i}ve PTMs in vivo. To evaluate the protective efficacy of LEN PrEP, na{\"i}ve 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.",

keywords = "Capsid, HIV, Macaque, Nonhuman primate, Pre-exposure prophylaxis, PrEP",

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

note = "Funding Information: 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.The authors thank George Muthua and the animal care staff of the Laboratory Animal Sciences Program, Frederick National Laboratory, for expert animal care and support. The authors also thank Brandon Keele for assistance generating viral CA amino acid sequence alignments and Pamela Beltowski for assistance with figure production. The anti-CD8 alpha [MT807R1] antibody used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116). This study was funded in part from Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab, in part by NIH grant R01AI078788 (to TH), and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Funding Information: The authors thank George Muthua and the animal care staff of the Laboratory Animal Sciences Program, Frederick National Laboratory, for expert animal care and support. The authors also thank Brandon Keele for assistance generating viral CA amino acid sequence alignments and Pamela Beltowski for assistance with figure production. The anti-CD8 alpha [MT807R1] antibody used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116). This study was funded in part from Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab , in part by NIH grant R01AI078788 (to TH), and in part with federal funds from the National Cancer Institute , National Institutes of Health , under Contract No. 75N91019D00024 / HHSN261201500003I . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = sep,

doi = "10.1016/j.ebiom.2023.104764",

language = "English (US)",

volume = "95",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

Swanstrom, AE, Gorelick, RJ, Welker, JL, Schmidt, F, Lu, B, Wang, K, Rowe, W, Breed, MW, Killoran, KE, Kramer, JA, Donohue, D, Roser, JD, Bieniasz, PD, Hatziioannou, T, Pyle, C, Thomas, JA, Trubey, CM, Zheng, J, Blair, W, Yant, SR, Lifson, JD & Del Prete, GQ 2023, 'Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV', EBioMedicine, vol. 95, 104764. https://doi.org/10.1016/j.ebiom.2023.104764

TY - JOUR

T1 - Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV

AU - Swanstrom, Adrienne E.

AU - Gorelick, Robert J.

AU - Welker, Jorden L.

AU - Schmidt, Fabian

AU - Lu, Bing

AU - Wang, Kelly

AU - Rowe, William

AU - Breed, Matthew W.

AU - Killoran, Kristin E.

AU - Kramer, Joshua A.

AU - Donohue, Duncan

AU - Roser, James D.

AU - Bieniasz, Paul D.

AU - Hatziioannou, Theodora

AU - Pyle, Cathi

AU - Thomas, James A.

AU - Trubey, Charles M.

AU - Zheng, Jim

AU - Blair, Wade

AU - Yant, Stephen R.

AU - Lifson, Jeffrey D.

AU - Del Prete, Gregory Q.

N1 - Funding Information: 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.The authors thank George Muthua and the animal care staff of the Laboratory Animal Sciences Program, Frederick National Laboratory, for expert animal care and support. The authors also thank Brandon Keele for assistance generating viral CA amino acid sequence alignments and Pamela Beltowski for assistance with figure production. The anti-CD8 alpha [MT807R1] antibody used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116). This study was funded in part from Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab, in part by NIH grant R01AI078788 (to TH), and in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Funding Information: The authors thank George Muthua and the animal care staff of the Laboratory Animal Sciences Program, Frederick National Laboratory, for expert animal care and support. The authors also thank Brandon Keele for assistance generating viral CA amino acid sequence alignments and Pamela Beltowski for assistance with figure production. The anti-CD8 alpha [MT807R1] antibody used in this study was provided by the NIH Nonhuman Primate Reagent Resource (P40 OD028116). This study was funded in part from Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab , in part by NIH grant R01AI078788 (to TH), and in part with federal funds from the National Cancer Institute , National Institutes of Health , under Contract No. 75N91019D00024 / HHSN261201500003I . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Publisher Copyright: © 2023 The Author(s)

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

KW - Capsid

KW - HIV

KW - Macaque

KW - Nonhuman primate

KW - Pre-exposure prophylaxis

KW - PrEP

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U2 - 10.1016/j.ebiom.2023.104764

DO - 10.1016/j.ebiom.2023.104764

M3 - Article

C2 - 37625266

AN - SCOPUS:85169439273

SN - 2352-3964

VL - 95

JO - EBioMedicine

JF - EBioMedicine

M1 - 104764

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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