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Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay

BACKGROUND: Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies using a limited number of clinical isolates showed that there wa...

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Autores principales: Gartland, Margaret, Zhou, Nannan, Stewart, Eugene, Pierce, Amy, Clark, Andrew, Ackerman, Peter, Llamoso, Cyril, Lataillade, Max, Krystal, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879148/
https://www.ncbi.nlm.nih.gov/pubmed/33241285
http://dx.doi.org/10.1093/jac/dkaa474
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author Gartland, Margaret
Zhou, Nannan
Stewart, Eugene
Pierce, Amy
Clark, Andrew
Ackerman, Peter
Llamoso, Cyril
Lataillade, Max
Krystal, Mark
author_facet Gartland, Margaret
Zhou, Nannan
Stewart, Eugene
Pierce, Amy
Clark, Andrew
Ackerman, Peter
Llamoso, Cyril
Lataillade, Max
Krystal, Mark
author_sort Gartland, Margaret
collection PubMed
description BACKGROUND: Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies using a limited number of clinical isolates showed that there was intrinsic variability in their susceptibility to temsavir. OBJECTIVES: Here, an analysis was performed using all clinical isolates analysed in the Monogram Biosciences PhenoSense(®) Entry assay as part of the development programme. METHODS: In total, 1337 individual envelopes encompassing 20 different HIV-1 subtypes were examined for their susceptibility to temsavir. However, only seven subtypes (B, C, F1, A, [B, F1], BF and A1) were present more than five times, with subtype B (881 isolates) and subtype C (156 isolates) having the largest numbers. RESULTS: As expected, variability in susceptibility was observed within all subtypes. However, for the great majority of these viruses, temsavir was highly potent, with most viruses exhibiting IC(50)s <10 nM. One exception was CRF01_AE viruses, where all five isolates exhibited IC(50)s >100 nM. For the 607 isolates where tropism data were available, geometric mean temsavir IC(50) values were remarkably similar for CCR5-, CXCR4- and dual mixed-tropic envelopes from infected individuals. CONCLUSIONS: These data show that HIV-1 viruses from most subtypes are highly susceptible to temsavir and that temsavir susceptibility is independent of tropism.
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spelling pubmed-78791482021-02-17 Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay Gartland, Margaret Zhou, Nannan Stewart, Eugene Pierce, Amy Clark, Andrew Ackerman, Peter Llamoso, Cyril Lataillade, Max Krystal, Mark J Antimicrob Chemother Original Research BACKGROUND: Fostemsavir is a prodrug of a first-in-class HIV-1 attachment inhibitor, temsavir, that binds to gp120 and blocks attachment to the host-cell CD4 receptor, preventing entry and infection of the target cell. Previous studies using a limited number of clinical isolates showed that there was intrinsic variability in their susceptibility to temsavir. OBJECTIVES: Here, an analysis was performed using all clinical isolates analysed in the Monogram Biosciences PhenoSense(®) Entry assay as part of the development programme. METHODS: In total, 1337 individual envelopes encompassing 20 different HIV-1 subtypes were examined for their susceptibility to temsavir. However, only seven subtypes (B, C, F1, A, [B, F1], BF and A1) were present more than five times, with subtype B (881 isolates) and subtype C (156 isolates) having the largest numbers. RESULTS: As expected, variability in susceptibility was observed within all subtypes. However, for the great majority of these viruses, temsavir was highly potent, with most viruses exhibiting IC(50)s <10 nM. One exception was CRF01_AE viruses, where all five isolates exhibited IC(50)s >100 nM. For the 607 isolates where tropism data were available, geometric mean temsavir IC(50) values were remarkably similar for CCR5-, CXCR4- and dual mixed-tropic envelopes from infected individuals. CONCLUSIONS: These data show that HIV-1 viruses from most subtypes are highly susceptible to temsavir and that temsavir susceptibility is independent of tropism. Oxford University Press 2020-11-30 /pmc/articles/PMC7879148/ /pubmed/33241285 http://dx.doi.org/10.1093/jac/dkaa474 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Research
Gartland, Margaret
Zhou, Nannan
Stewart, Eugene
Pierce, Amy
Clark, Andrew
Ackerman, Peter
Llamoso, Cyril
Lataillade, Max
Krystal, Mark
Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay
title Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay
title_full Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay
title_fullStr Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay
title_full_unstemmed Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay
title_short Susceptibility of global HIV-1 clinical isolates to fostemsavir using the PhenoSense(®) Entry assay
title_sort susceptibility of global hiv-1 clinical isolates to fostemsavir using the phenosense(®) entry assay
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879148/
https://www.ncbi.nlm.nih.gov/pubmed/33241285
http://dx.doi.org/10.1093/jac/dkaa474
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