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Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity
Anti-HIV microbicides are being investigated in clinical trials and understanding how promising strategies work, coincident with demonstrating efficacy in vivo, is central to advancing new generation microbicides. We evaluated Carraguard® and a new generation Carraguard-based formulation containing...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2525816/ https://www.ncbi.nlm.nih.gov/pubmed/18776937 http://dx.doi.org/10.1371/journal.pone.0003162 |
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author | Turville, Stuart G. Aravantinou, Meropi Miller, Todd Kenney, Jessica Teitelbaum, Aaron Hu, Lieyu Chudolij, Anne Zydowsky, Tom M. Piatak, Michael Bess, Julian W. Lifson, Jeffrey D. Blanchard, James Gettie, Agegnehu Robbiani, Melissa |
author_facet | Turville, Stuart G. Aravantinou, Meropi Miller, Todd Kenney, Jessica Teitelbaum, Aaron Hu, Lieyu Chudolij, Anne Zydowsky, Tom M. Piatak, Michael Bess, Julian W. Lifson, Jeffrey D. Blanchard, James Gettie, Agegnehu Robbiani, Melissa |
author_sort | Turville, Stuart G. |
collection | PubMed |
description | Anti-HIV microbicides are being investigated in clinical trials and understanding how promising strategies work, coincident with demonstrating efficacy in vivo, is central to advancing new generation microbicides. We evaluated Carraguard® and a new generation Carraguard-based formulation containing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (PC-817). Since dendritic cells (DCs) are believed to be important in HIV transmission, the formulations were tested for the ability to limit DC-driven infection in vitro versus vaginal infection of macaques with RT-SHIV (SIVmac239 bearing HIV reverse transcriptase). Carraguard showed limited activity against cell-free and mature DC-driven RT-SHIV infections and, surprisingly, low doses of Carraguard enhanced infection. However, nanomolar amounts of MIV-150 overcame enhancement and blocked DC-transmitted infection. In contrast, Carraguard impeded infection of immature DCs coincident with DC maturation. Despite this variable activity in vitro, Carraguard and PC-817 prevented vaginal transmission of RT-SHIV when applied 30 min prior to challenge. PC-817 appeared no more effective than Carraguard in vivo, due to the limited activity of a single dose of MIV-150 and the dominant barrier effect of Carraguard. However, 3 doses of MIV-150 in placebo gel at and around challenge limited vaginal infection, demonstrating the potential activity of a topically applied NNRTI. These data demonstrate discordant observations when comparing in vitro and in vivo efficacy of Carraguard-based microbicides, highlighting the difficulties in testing putative anti-viral strategies in vitro to predict in vivo activity. This work also underscores the potential of Carraguard-based formulations for the delivery of anti-viral drugs to prevent vaginal HIV infection. |
format | Text |
id | pubmed-2525816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-25258162008-09-08 Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity Turville, Stuart G. Aravantinou, Meropi Miller, Todd Kenney, Jessica Teitelbaum, Aaron Hu, Lieyu Chudolij, Anne Zydowsky, Tom M. Piatak, Michael Bess, Julian W. Lifson, Jeffrey D. Blanchard, James Gettie, Agegnehu Robbiani, Melissa PLoS One Research Article Anti-HIV microbicides are being investigated in clinical trials and understanding how promising strategies work, coincident with demonstrating efficacy in vivo, is central to advancing new generation microbicides. We evaluated Carraguard® and a new generation Carraguard-based formulation containing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (PC-817). Since dendritic cells (DCs) are believed to be important in HIV transmission, the formulations were tested for the ability to limit DC-driven infection in vitro versus vaginal infection of macaques with RT-SHIV (SIVmac239 bearing HIV reverse transcriptase). Carraguard showed limited activity against cell-free and mature DC-driven RT-SHIV infections and, surprisingly, low doses of Carraguard enhanced infection. However, nanomolar amounts of MIV-150 overcame enhancement and blocked DC-transmitted infection. In contrast, Carraguard impeded infection of immature DCs coincident with DC maturation. Despite this variable activity in vitro, Carraguard and PC-817 prevented vaginal transmission of RT-SHIV when applied 30 min prior to challenge. PC-817 appeared no more effective than Carraguard in vivo, due to the limited activity of a single dose of MIV-150 and the dominant barrier effect of Carraguard. However, 3 doses of MIV-150 in placebo gel at and around challenge limited vaginal infection, demonstrating the potential activity of a topically applied NNRTI. These data demonstrate discordant observations when comparing in vitro and in vivo efficacy of Carraguard-based microbicides, highlighting the difficulties in testing putative anti-viral strategies in vitro to predict in vivo activity. This work also underscores the potential of Carraguard-based formulations for the delivery of anti-viral drugs to prevent vaginal HIV infection. Public Library of Science 2008-09-08 /pmc/articles/PMC2525816/ /pubmed/18776937 http://dx.doi.org/10.1371/journal.pone.0003162 Text en Turville et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Turville, Stuart G. Aravantinou, Meropi Miller, Todd Kenney, Jessica Teitelbaum, Aaron Hu, Lieyu Chudolij, Anne Zydowsky, Tom M. Piatak, Michael Bess, Julian W. Lifson, Jeffrey D. Blanchard, James Gettie, Agegnehu Robbiani, Melissa Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity |
title | Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity |
title_full | Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity |
title_fullStr | Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity |
title_full_unstemmed | Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity |
title_short | Efficacy of Carraguard®-Based Microbicides In Vivo Despite Variable In Vitro Activity |
title_sort | efficacy of carraguard®-based microbicides in vivo despite variable in vitro activity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2525816/ https://www.ncbi.nlm.nih.gov/pubmed/18776937 http://dx.doi.org/10.1371/journal.pone.0003162 |
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