Maraviroc and reverse transcriptase inhibitors combinations as potential pre-exposure prophylaxis candidates
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Objective: Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a program to develop an effective prevention strategy, we performed an ex-vivo preclinical evaluation to determine the efficacy of multiple double combinations of maraviroc (MVC) and reverse transcriptase inhibitors (RTIs).
Design: The entry inhibitor, MVC, a nucleotide RTI, tenofovir and two non-nucleoside RTIs, UC781 and TMC120 (dapivirine, DPV), were used in double, combinations against a panel of CCR5-using clade B and clade C HIV-1 isolates and against MVC-escape variants. A gel-formulated version of MVC-DPV combination was also tested.
Methods: Indicator cells, cocultures of immature dendritic cells with CD4+T cells, and colorectal tissue explants were used to assess antiviral activity of drug combinations.
Results: All dual MVC-RTI combinations tested inhibited MVC-sensitive and resistant isolates in cellular and colorectal explants models. All the combinations were positive with no reduction in the activity of MVC. In tissue explants, the combinations against all viral isolates tested produced an increase in the activity of MVC. An initial gel-formulation of MVC-DPV combination showed greater and prolonged antiviral activity of MVC in mucosal tissue explants.
Conclusion: This study demonstrates that combinations based on antiretroviral drugs inhibiting HIV transmission at viral entry and reverse transcription have potential as prevention strategies against colorectal transmission of HIV-1 including MVC-resistant isolates. Preclinical evaluation with colorectal tissue explants indicates that a gel-formulation of MVC-DPV is an effective candidate colorectal microbicide.
Design: The entry inhibitor, MVC, a nucleotide RTI, tenofovir and two non-nucleoside RTIs, UC781 and TMC120 (dapivirine, DPV), were used in double, combinations against a panel of CCR5-using clade B and clade C HIV-1 isolates and against MVC-escape variants. A gel-formulated version of MVC-DPV combination was also tested.
Methods: Indicator cells, cocultures of immature dendritic cells with CD4+T cells, and colorectal tissue explants were used to assess antiviral activity of drug combinations.
Results: All dual MVC-RTI combinations tested inhibited MVC-sensitive and resistant isolates in cellular and colorectal explants models. All the combinations were positive with no reduction in the activity of MVC. In tissue explants, the combinations against all viral isolates tested produced an increase in the activity of MVC. An initial gel-formulation of MVC-DPV combination showed greater and prolonged antiviral activity of MVC in mucosal tissue explants.
Conclusion: This study demonstrates that combinations based on antiretroviral drugs inhibiting HIV transmission at viral entry and reverse transcription have potential as prevention strategies against colorectal transmission of HIV-1 including MVC-resistant isolates. Preclinical evaluation with colorectal tissue explants indicates that a gel-formulation of MVC-DPV is an effective candidate colorectal microbicide.
Date Issued
2016-04-24
Date Acceptance
2016-01-18
Citation
AIDS, 2016, 30 (7), pp.1015-1025
ISSN
0269-9370
Publisher
Lippincott, Williams & Wilkins
Start Page
1015
End Page
1025
Journal / Book Title
AIDS
Volume
30
Issue
7
Copyright Statement
This is the accepted version and not the final version of record. The final published version can be found at 'Maraviroc and reverse transcriptase inhibitors combinations as potential preexposure prophylaxis candidates'
Herrera, Carolina; Armanasco, Naomi; García-Pérez, Javier; Ziprin, Paul; Olejniczak, Natalia; Alcamí, José; Nuttall, Jeremy; Shattock, Robin J. AIDS
Issue: Volume 30(7), 24 April 2016, p 1015–1025. https://dx.doi.org/10.1097/QAD.0000000000001043
Copyright: Copyright © 2016 Wolters Kluwer Health, Inc.
Herrera, Carolina; Armanasco, Naomi; García-Pérez, Javier; Ziprin, Paul; Olejniczak, Natalia; Alcamí, José; Nuttall, Jeremy; Shattock, Robin J. AIDS
Issue: Volume 30(7), 24 April 2016, p 1015–1025. https://dx.doi.org/10.1097/QAD.0000000000001043
Copyright: Copyright © 2016 Wolters Kluwer Health, Inc.
Sponsor
Commission of the European Communities
International Partnership for Microbicides, Inc.
International Partnership for Microbicides, Inc.
Commission of the European Communities
Grant Number
242135
n/a
na
305316
Subjects
Virology
06 Biological Sciences
11 Medical And Health Sciences
17 Psychology And Cognitive Sciences
Publication Status
Published