The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.

<h4>Background</h4>RC-101 is a congener of the antiretroviral peptide retrocyclin, which we and others have reported is active against clinical HIV-1 isolates from all major clades, does not hemagglutinate, and is non-toxic and non-inflammatory in cervicovaginal cell culture. Herein, fil...

Full description

Saved in:
Bibliographic Details
Main Authors: Alexander M Cole, Dorothy L Patton, Lisa C Rohan, Amy L Cole, Yvonne Cosgrove-Sweeney, Nicole A Rogers, Deena Ratner, Alexandra B Sassi, Carol Lackman-Smith, Patrick Tarwater, Bharat Ramratnam, Piotr Ruchala, Robert I Lehrer, Alan J Waring, Phalguni Gupta
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2010-11-01
Series:PLoS ONE
Online Access:https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015111&type=printable
Tags: Add Tag
No Tags, Be the first to tag this record!
_version_ 1832592752585474048
author Alexander M Cole
Dorothy L Patton
Lisa C Rohan
Amy L Cole
Yvonne Cosgrove-Sweeney
Nicole A Rogers
Deena Ratner
Alexandra B Sassi
Carol Lackman-Smith
Patrick Tarwater
Bharat Ramratnam
Piotr Ruchala
Robert I Lehrer
Alan J Waring
Phalguni Gupta
author_facet Alexander M Cole
Dorothy L Patton
Lisa C Rohan
Amy L Cole
Yvonne Cosgrove-Sweeney
Nicole A Rogers
Deena Ratner
Alexandra B Sassi
Carol Lackman-Smith
Patrick Tarwater
Bharat Ramratnam
Piotr Ruchala
Robert I Lehrer
Alan J Waring
Phalguni Gupta
author_sort Alexander M Cole
collection DOAJ
description <h4>Background</h4>RC-101 is a congener of the antiretroviral peptide retrocyclin, which we and others have reported is active against clinical HIV-1 isolates from all major clades, does not hemagglutinate, and is non-toxic and non-inflammatory in cervicovaginal cell culture. Herein, film-formulated RC-101 was assessed for its antiviral activity in vitro, safety in vivo, retention in the cervix and vagina, and ability to remain active against HIV-1 and SHIV after intravaginal application in macaques.<h4>Methodology/principal findings</h4>RC-101 was formulated as a quick-dissolving film (2000 µg/film), retained complete activity in vitro as compared to unformulated peptide, and was applied intravaginally in six pigtailed macaques daily for four days. At one and four days following the final application, the presence of RC-101 was assessed in peripheral blood, cervicovaginal lavage, cytobrushed cervicovaginal cells, and biopsied cervical and vaginal tissues by quantitative western blots. One day following the last film application, cervical biopsies from RC-101-exposed and placebo-controlled macaques were collected and were subjected to challenge with RT-SHIV in an ex vivo organ culture model. RC-101 peptide was detected primarily in the cytobrush and biopsied cervical and vaginal tissues, with little to no peptide detected in lavage samples, suggesting that the peptide was associated with the cervicovaginal epithelia. RC-101 remained in the tissues and cytobrush samples up to four days post-application, yet was not detected in any sera or plasma samples. RC-101, extracted from cytobrushes obtained one day post-application, remained active against HIV-1 BaL. Importantly, cervical biopsies from RC-101-treated animals reduced RT-SHIV replication in ex vivo organ culture as compared to placebo-treated animals.<h4>Conclusions/significance</h4>Formulated RC-101 was stable in vivo and was retained in the mucosa. The presence of antivirally active RC-101 after five days in vivo suggests that RC-101 would be an important molecule to develop further as a topical microbicide to prevent HIV-1 transmission.
format Article
id doaj-art-e2d818de95fa4083945b9aaca638183a
institution Kabale University
issn 1932-6203
language English
publishDate 2010-11-01
publisher Public Library of Science (PLoS)
record_format Article
series PLoS ONE
spelling doaj-art-e2d818de95fa4083945b9aaca638183a2025-01-21T05:31:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-11-01511e1511110.1371/journal.pone.0015111The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.Alexander M ColeDorothy L PattonLisa C RohanAmy L ColeYvonne Cosgrove-SweeneyNicole A RogersDeena RatnerAlexandra B SassiCarol Lackman-SmithPatrick TarwaterBharat RamratnamPiotr RuchalaRobert I LehrerAlan J WaringPhalguni Gupta<h4>Background</h4>RC-101 is a congener of the antiretroviral peptide retrocyclin, which we and others have reported is active against clinical HIV-1 isolates from all major clades, does not hemagglutinate, and is non-toxic and non-inflammatory in cervicovaginal cell culture. Herein, film-formulated RC-101 was assessed for its antiviral activity in vitro, safety in vivo, retention in the cervix and vagina, and ability to remain active against HIV-1 and SHIV after intravaginal application in macaques.<h4>Methodology/principal findings</h4>RC-101 was formulated as a quick-dissolving film (2000 µg/film), retained complete activity in vitro as compared to unformulated peptide, and was applied intravaginally in six pigtailed macaques daily for four days. At one and four days following the final application, the presence of RC-101 was assessed in peripheral blood, cervicovaginal lavage, cytobrushed cervicovaginal cells, and biopsied cervical and vaginal tissues by quantitative western blots. One day following the last film application, cervical biopsies from RC-101-exposed and placebo-controlled macaques were collected and were subjected to challenge with RT-SHIV in an ex vivo organ culture model. RC-101 peptide was detected primarily in the cytobrush and biopsied cervical and vaginal tissues, with little to no peptide detected in lavage samples, suggesting that the peptide was associated with the cervicovaginal epithelia. RC-101 remained in the tissues and cytobrush samples up to four days post-application, yet was not detected in any sera or plasma samples. RC-101, extracted from cytobrushes obtained one day post-application, remained active against HIV-1 BaL. Importantly, cervical biopsies from RC-101-treated animals reduced RT-SHIV replication in ex vivo organ culture as compared to placebo-treated animals.<h4>Conclusions/significance</h4>Formulated RC-101 was stable in vivo and was retained in the mucosa. The presence of antivirally active RC-101 after five days in vivo suggests that RC-101 would be an important molecule to develop further as a topical microbicide to prevent HIV-1 transmission.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015111&type=printable
spellingShingle Alexander M Cole
Dorothy L Patton
Lisa C Rohan
Amy L Cole
Yvonne Cosgrove-Sweeney
Nicole A Rogers
Deena Ratner
Alexandra B Sassi
Carol Lackman-Smith
Patrick Tarwater
Bharat Ramratnam
Piotr Ruchala
Robert I Lehrer
Alan J Waring
Phalguni Gupta
The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.
PLoS ONE
title The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.
title_full The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.
title_fullStr The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.
title_full_unstemmed The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.
title_short The formulated microbicide RC-101 was safe and antivirally active following intravaginal application in pigtailed macaques.
title_sort formulated microbicide rc 101 was safe and antivirally active following intravaginal application in pigtailed macaques
url https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015111&type=printable
work_keys_str_mv AT alexandermcole theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT dorothylpatton theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT lisacrohan theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT amylcole theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT yvonnecosgrovesweeney theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT nicolearogers theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT deenaratner theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT alexandrabsassi theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT carollackmansmith theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT patricktarwater theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT bharatramratnam theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT piotrruchala theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT robertilehrer theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT alanjwaring theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT phalgunigupta theformulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT alexandermcole formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT dorothylpatton formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT lisacrohan formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT amylcole formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT yvonnecosgrovesweeney formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT nicolearogers formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT deenaratner formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT alexandrabsassi formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT carollackmansmith formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT patricktarwater formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT bharatramratnam formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT piotrruchala formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT robertilehrer formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT alanjwaring formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques
AT phalgunigupta formulatedmicrobiciderc101wassafeandantivirallyactivefollowingintravaginalapplicationinpigtailedmacaques