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

HIV-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 activit...

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Autores principales: Lachlan 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
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spelling oai:doaj.org-article:d97c6377d27544618061aac3fbdc631d2021-11-18T07:49:11ZThe NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.1932-620310.1371/journal.pone.0062196https://doaj.org/article/d97c6377d27544618061aac3fbdc631d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23614033/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203HIV-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.Lachlan R GrayGilda TachedjianAnne M EllettMichael J RocheWan-Jung ChengGilles J GuilleminBruce J BrewStuart G TurvilleSteve L WesselinghPaul R GorryMelissa J ChurchillPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e62196 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Lachlan 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
The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
description HIV-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.
format article
author Lachlan 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
author_facet Lachlan 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
author_sort Lachlan R Gray
title The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
title_short The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
title_full The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
title_fullStr The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
title_full_unstemmed The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.
title_sort nrtis lamivudine, stavudine and zidovudine have reduced hiv-1 inhibitory activity in astrocytes.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/d97c6377d27544618061aac3fbdc631d
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