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In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides

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dc.contributor.author Van Herrewege, Y. en_US
dc.contributor.author Michiels, J. en_US
dc.contributor.author Van Roey, J. en_US
dc.contributor.author Fransen, K. en_US
dc.contributor.author Kestens, L. en_US
dc.contributor.author Balzarini, J. en_US
dc.contributor.author Lewi, P. en_US
dc.contributor.author Vanham, G. en_US
dc.contributor.author Janssen, P. en_US
dc.date.accessioned 2007-12-06T14:48:45Z
dc.date.available 2007-12-06T14:48:45Z
dc.date.issued 2004 en_US
dc.identifier.issn 0066-4804 en_US
dc.identifier.doi http://dx.doi.org/10.1128/AAC.48.1.337-339.2004
dc.identifier.other ITG-M1A en_US
dc.identifier.other ITG-M2B en_US
dc.identifier.other ITG-M4A en_US
dc.identifier.other ITG-M5A en_US
dc.identifier.other ITG-M8A en_US
dc.identifier.other MICRO en_US
dc.identifier.other U-IMMUN en_US
dc.identifier.other U-VIROL en_US
dc.identifier.other JIF en_US
dc.identifier.other DOI en_US
dc.identifier.other ABSTRACT en_US
dc.identifier.uri http://hdl.handle.net/10390/2044
dc.description.abstract An in vitro model of monocyte-derived dendritic cells (MO-DC) and CD4(+) T cells, representing the primary targets of sexual human immunodeficiency virus (HIV) transmission, was used to evaluate the antiviral and immune suppressive activity of new classes of nonnucleoside reverse transcriptase inhibitors, diaryltriazines (DATAs) and diarylpyrimidines (DAPYs), compared to the reference compounds UC-781 and PMPA. Antiviral activity (as reflected by the 50% effective concentration [EC(50)]) was determined by treating HIV-infected MO-DC/CD4(+)-T-cell cocultures with a dose range of a compound during 14 days, followed by analysis of supernatants in HIV p24 antigen enzyme-linked immunosorbent assay. A limited, 24-h treatment evaluated the compounds as microbicides. Viral rescue was evaluated in a PCR by monitoring proviral DNA in secondary cultures with phytohemagglutinin-interleukin-2 blasts. We determined 50% immunosuppressive concentrations in mixed leukocyte cultures of MO-DC and allogeneic T cells, with compound either continuously present or present only during the first 24 h. The EC(50) values of DATA and DAPY compounds ranged from 0.05 to 3 nM compared to 50 nM for UC-781 and 89 nM for PMPA. When evaluated in the "microbicide" setting, the most potent compounds completely blocked HIV infection at 10 to 100 nM. The immunosuppressive concentrations were well above the EC(50), resulting in favorable therapeutic indices for all compounds tested. The DATA and DAPY compounds described here are more potent than earlier reverse transcriptase inhibitors and show favorable pharmacological profiles in vitro. They could strengthen the antiretroviral armamentarium and might be useful as microbicides. en_US
dc.language English en_US
dc.subject Viral diseases en_US
dc.subject HIV en_US
dc.subject AIDS en_US
dc.subject Microbicides en_US
dc.subject Reverse transcriptase inhibitors en_US
dc.subject Efficacy en_US
dc.title In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides en_US
dc.type Article en_US
dc.citation.issue 1 en_US
dc.citation.jtitle Antimicrobial Agents and Chemotherapy en_US
dc.citation.volume 48 en_US
dc.citation.pages 337-339 en_US
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/15388420
dc.citation.jabbreviation Antimicrob Agents Chemother en_US


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