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Mode of Coreceptor Use by R5 HIV Type 1 Correlates with Disease Stage: A Study of Paired Plasma and Cerebrospinal Fluid Isolates.

Karlsson, Ulf LU ; Antonsson, Liselotte LU ; Repits, Johanna LU ; Medstrand, Patrik LU ; Owman, Christer LU ; Kidd-Ljunggren, Karin LU ; Hagberg, Lars LU ; Svennerholm, Bo; Jansson, Marianne LU and Gisslén, Magnus, et al. (2009) In AIDS Research and Human Retroviruses 25(12). p.1297-1305
Abstract
Abstract Through the use of chimeric CXCR4/CCR5 receptors we have previously shown that CCR5-tropic (R5) HIV-1 isolates acquire a more flexible receptor use over time, and that this links to a reduced viral susceptibility to inhibition by the CCR5 ligand RANTES. These findings may have relevance with regards to the efficacy of antiretroviral compounds that target CCR5/virus interactions. Compartmentalized discrepancies in coreceptor use may occur, which could also affect the efficacy of these compounds at specific anatomical sites, such as within the CNS. In this cross-sectional study we have used wild-type CCR5 and CXCR4 as well as chimeric CXCR4/CCR5 receptors to characterize coreceptor use by paired plasma and cerebrospinal fluid (CSF)... (More)
Abstract Through the use of chimeric CXCR4/CCR5 receptors we have previously shown that CCR5-tropic (R5) HIV-1 isolates acquire a more flexible receptor use over time, and that this links to a reduced viral susceptibility to inhibition by the CCR5 ligand RANTES. These findings may have relevance with regards to the efficacy of antiretroviral compounds that target CCR5/virus interactions. Compartmentalized discrepancies in coreceptor use may occur, which could also affect the efficacy of these compounds at specific anatomical sites, such as within the CNS. In this cross-sectional study we have used wild-type CCR5 and CXCR4 as well as chimeric CXCR4/CCR5 receptors to characterize coreceptor use by paired plasma and cerebrospinal fluid (CSF) isolates from 28 HIV-1-infected individuals. Furthermore, selected R5 isolates, with varying chimeric receptor use, were tested for sensitivity to inhibition by the CCR5 antagonist TAK-779. Discordant CSF/plasma virus coreceptor use was found in 10/28 patients. Low CD4(+) T cell counts correlated strongly with a more flexible mode of R5 virus CCR5 usage, as disclosed by an increased ability to utilize chimeric CXCR4/CCR5 receptors, specifically receptor FC-2. Importantly, an elevated ability to utilize chimeric receptors correlated with a reduced susceptibility to inhibition by TAK-779. Our findings show that a discordant CSF and plasma virus coreceptor use is not uncommon. Furthermore, we provide support for an emerging paradigm, where the acquisition of a more flexible mode of CCR5 usage is a key event in R5 virus pathogenesis. This may, in turn, negatively impact the efficacy of CCR5 antagonist treatment in late stage HIV-1 disease. (Less)
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publication status
published
subject
in
AIDS Research and Human Retroviruses
volume
25
issue
12
pages
1297 - 1305
publisher
Mary Ann Liebert, Inc.
external identifiers
  • wos:000272608400013
  • pmid:20001314
  • scopus:73149096528
ISSN
1931-8405
DOI
10.1089/aid.2009.0069
language
English
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yes
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d511080f-dbc0-436a-910c-7a37f5c720e9 (old id 1523675)
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http://www.ncbi.nlm.nih.gov/pubmed/20001314?dopt=Abstract
date added to LUP
2010-01-14 13:23:17
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2017-01-01 07:33:31
@article{d511080f-dbc0-436a-910c-7a37f5c720e9,
  abstract     = {Abstract Through the use of chimeric CXCR4/CCR5 receptors we have previously shown that CCR5-tropic (R5) HIV-1 isolates acquire a more flexible receptor use over time, and that this links to a reduced viral susceptibility to inhibition by the CCR5 ligand RANTES. These findings may have relevance with regards to the efficacy of antiretroviral compounds that target CCR5/virus interactions. Compartmentalized discrepancies in coreceptor use may occur, which could also affect the efficacy of these compounds at specific anatomical sites, such as within the CNS. In this cross-sectional study we have used wild-type CCR5 and CXCR4 as well as chimeric CXCR4/CCR5 receptors to characterize coreceptor use by paired plasma and cerebrospinal fluid (CSF) isolates from 28 HIV-1-infected individuals. Furthermore, selected R5 isolates, with varying chimeric receptor use, were tested for sensitivity to inhibition by the CCR5 antagonist TAK-779. Discordant CSF/plasma virus coreceptor use was found in 10/28 patients. Low CD4(+) T cell counts correlated strongly with a more flexible mode of R5 virus CCR5 usage, as disclosed by an increased ability to utilize chimeric CXCR4/CCR5 receptors, specifically receptor FC-2. Importantly, an elevated ability to utilize chimeric receptors correlated with a reduced susceptibility to inhibition by TAK-779. Our findings show that a discordant CSF and plasma virus coreceptor use is not uncommon. Furthermore, we provide support for an emerging paradigm, where the acquisition of a more flexible mode of CCR5 usage is a key event in R5 virus pathogenesis. This may, in turn, negatively impact the efficacy of CCR5 antagonist treatment in late stage HIV-1 disease.},
  author       = {Karlsson, Ulf and Antonsson, Liselotte and Repits, Johanna and Medstrand, Patrik and Owman, Christer and Kidd-Ljunggren, Karin and Hagberg, Lars and Svennerholm, Bo and Jansson, Marianne and Gisslén, Magnus and Ljungberg, Bengt},
  issn         = {1931-8405},
  language     = {eng},
  number       = {12},
  pages        = {1297--1305},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {AIDS Research and Human Retroviruses},
  title        = {Mode of Coreceptor Use by R5 HIV Type 1 Correlates with Disease Stage: A Study of Paired Plasma and Cerebrospinal Fluid Isolates.},
  url          = {http://dx.doi.org/10.1089/aid.2009.0069},
  volume       = {25},
  year         = {2009},
}