Mode of Coreceptor Use by R5 HIV Type 1 Correlates with Disease Stage: A Study of Paired Plasma and Cerebrospinal Fluid Isolates
- 1 December 2009
- journal article
- research article
- Published by Mary Ann Liebert Inc in AIDS Research and Human Retroviruses
- Vol. 25 (12), 1297-1305
- https://doi.org/10.1089/aid.2009.0069
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.Keywords
This publication has 85 references indexed in Scilit:
- Persistent Intrathecal Immune Activation in HIV-1-Infected Individuals on Antiretroviral TherapyJAIDS Journal of Acquired Immune Deficiency Syndromes, 2008
- Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous SystemArchives of Neurology, 2008
- Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDSRetrovirology, 2007
- Updated research nosology for HIV-associated neurocognitive disordersNeurology, 2007
- Development and Characterization of a Novel Single-Cycle Recombinant-Virus Assay To Determine Human Immunodeficiency Virus Type 1 Coreceptor TropismAntimicrobial Agents and Chemotherapy, 2007
- Coevolution of RANTES Sensitivity and Mode of CCR5 Receptor Use by Human Immunodeficiency Virus Type 1 of the R5 PhenotypeJournal of Virology, 2004
- Molecular mapping of epitopes for interaction of HIV-1 as well as natural ligands with the chemokine receptors, CCR5 and CXCR4AIDS, 2003
- HIV biological variability unveiledAIDS, 2003
- Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4Current Biology, 1998
- Specific Tropism of HIV-1 for Microglial Cells in Primary Human Brain CulturesScience, 1990