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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 orcid ; 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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organization
publishing date
type
Contribution to journal
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
  • pmid:20001314
ISSN
1931-8405
DOI
10.1089/aid.2009.0069
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Infection Medicine (SUS) (013008000), Reconstructive Surgery (013240300), Molecular Virology (013212007), Division of Medical Microbiology (013250400), Drug Target Discovery (013212045)
id
d511080f-dbc0-436a-910c-7a37f5c720e9 (old id 1523675)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20001314?dopt=Abstract
date added to LUP
2016-04-04 07:50:25
date last changed
2022-02-20 20:56:52
@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}},
  doi          = {{10.1089/aid.2009.0069}},
  volume       = {{25}},
  year         = {{2009}},
}