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The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes

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dc.contributor.authorGray, L.
dc.contributor.authorTachedjian, G.
dc.contributor.authorEllett, A.
dc.contributor.authorRoche, M.
dc.contributor.authorCheng, W.
dc.contributor.authorGuillemin, G.
dc.contributor.authorBrew, B.
dc.contributor.authorTurville, S.
dc.contributor.authorWesselingh, S.
dc.contributor.authorGorry, P.
dc.contributor.authorChurchill, M.
dc.contributor.editorMenéndez-Arias, L.
dc.date.issued2013
dc.description.abstractHIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens.
dc.description.statementofresponsibilityLachlan R. Gray, Gilda Tachedjian, Anne M. Ellett, Michael J. Roche, Wan-Jung Cheng, Gilles J. Guillemin, Bruce J. Brew, Stuart G. Turville, Steve L. Wesselingh, Paul R. Gorry, Melissa J. Churchill
dc.identifier.citationPLoS ONE, 2013; 8(4):e62196-1-e62196-7
dc.identifier.doi10.1371/journal.pone.0062196
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/2440/97108
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/603708
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/606967
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/543105
dc.rights© 2013 Gray et al. 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 credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0062196
dc.subjectAstrocytes
dc.subjectCell Line
dc.subjectHumans
dc.subjectHIV-1
dc.subjectStavudine
dc.subjectZidovudine
dc.subjectReverse Transcriptase Inhibitors
dc.subjectAnti-HIV Agents
dc.titleThe NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes
dc.typeJournal article
pubs.publication-statusPublished

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