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Human Immunodeficiency Virus Type 1 (cross-) resistance to non-nucleoside reverse transcriptase inhibitors currently under development as microbicides

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dc.contributor.author Selhorst, P.
dc.contributor.author Vazquez, A. C.
dc.contributor.author Terrazas-Aranda, K.
dc.contributor.author Michiels, J.
dc.contributor.author Vereecken, K.
dc.contributor.author Heyndrickx, L.
dc.contributor.author Weber, J.
dc.contributor.author Quiñones-Mateu, M. E.
dc.contributor.author Ariën, K. K.
dc.contributor.author Vanham, G.
dc.date.accessioned 2011-04-29T13:35:46Z
dc.date.available 2011-04-29T13:35:46Z
dc.date.issued 2011
dc.identifier.issn 0066-4804
dc.identifier.doi http://dx.doi.org/10.1128/AAC.01426-10
dc.identifier.other ITG-M1B
dc.identifier.other ITG-M3B
dc.identifier.other ITG-M4B
dc.identifier.other ITG-M5B
dc.identifier.other ITG-M6A
dc.identifier.other ITG-M9A
dc.identifier.other ITG-MLA
dc.identifier.other MICRO
dc.identifier.other U-VIROL
dc.identifier.other JIF
dc.identifier.other DOI
dc.identifier.other Abstract
dc.identifier.other UPD33
dc.identifier.uri http://hdl.handle.net/10390/6563
dc.description.abstract Microbicides based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect woman from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV+ woman, they could potentially select for viral resistance which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides which are inactive against NNRTI-resistant strains, might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by serial passage of three viral isolates from subtypes B, C, and CRF02_AG in activated peripheral blood mononuclear cells (PBMC) under increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) which are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development whereas resistance to UC781 emerged rapidly, similar to efavirenz and nevirapine. Phenotypically, the selected viruses appeared highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz) although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120 and MIV-160 to inhibit the in vitro selected NNRTI-resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT-recombinant NNRTI-resistant viruses (i.e., TMC120-r VI829, EFV-r VI829, MIV-160-r VI829, and EFV-r MP568) showed impairment in replicative fitness. Overall, these in vitro analyses demonstrate that, due to potential cross-resistance, the large scale introduction of mono-RTI-based microbicides should be considered with caution. en
dc.language English en
dc.subject Viral diseases en
dc.subject HIV en
dc.subject AIDS en
dc.subject Prevention en
dc.subject Microbicides en
dc.subject Non-nucleoside en
dc.subject Reverse transcriptase inhibitors en
dc.subject Cross-resistance en
dc.subject Women en
dc.subject Disease transmission, sexual en
dc.subject Transmission interruption en
dc.subject In vitro en
dc.subject Strains en
dc.subject CRF02_AG en
dc.subject Subtype B en
dc.subject Subtype C en
dc.subject Peripheral blood mononuclear cell (PBMC) en
dc.subject Virus replication en
dc.subject Laboratory techniques and procedures en
dc.title Human Immunodeficiency Virus Type 1 (cross-) resistance to non-nucleoside reverse transcriptase inhibitors currently under development as microbicides en
dc.type Article en
dc.citation.issue 4 en
dc.citation.jtitle Antimicrobial Agents and Chemotherapy en
dc.citation.volume 55 en
dc.citation.pages 1403-1413 en
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/21282453
dc.citation.jabbreviation Antimicrob Agents Chemother en


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