Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783650472680226816 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7879148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT gartlandmargaret susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT zhounannan susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT stewarteugene susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT pierceamy susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT clarkandrew susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT ackermanpeter susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT llamosocyril susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT lataillademax susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay AT krystalmark susceptibilityofglobalhiv1clinicalisolatestofostemsavirusingthephenosenseentryassay |