CCR5 density levels on primary CD4 T cells impact the replication and Enfuvirtide susceptibility of R5 HIV-1
- 1 June 2007
- journal article
- research article
- Published by Wolters Kluwer Health in AIDS
- Vol. 21 (10) , 1317-1322
- https://doi.org/10.1097/qad.0b013e32815278ea
Abstract
Objective and design: Studies in cell lines have demonstrated that CCR5 coreceptor levels influence the replication efficiency and Enfuvirtide (T-20) susceptibility of R5 HIV-1 strains. At present, however, the role that CCR5 levels on primary CD4 T cells – which are markedly lower than in cell lines and vary only ∼fivefold among most donors – may play in virus replication levels or susceptibility to T-20 is not known. In the present study we evaluated the impact of differences in CCR5 levels among donor CD4 T cells on the infection efficiency and T-20 susceptibility of R5 HIV-1. Methods: CD4 and CCR5 density levels were determined by Quantitative FACS analysis. Virus infectivity assays were conducted in cell lines and primary cells. Associations between coreceptor density, virus replication and T-20 sensitivity were tested using the Spearman's correlation test. Results: We found a positive correlation (r, 0.55; P = 0.011) between CCR5 density levels on primary CD4 T cells and replication of R5 HIV-1. In cell lines expressing physiologically relevant levels of CD4 and CCR5, T-20 was significantly more potent in cells with low CCR5 levels. In addition, T20 50% inhibitory concentrations for R5 HIV-1 replication varied ∼100-fold among primary cells from different donors and they were positively correlated with CCR5 density values (r, 0.84; P = 0.00004). Conclusions: These results suggest that CCR5 density levels in HIV-1 patients may impact the activity of T-20 against R5 strains and that therapeutic approaches to alter CCR5 density may potentiate T-20.Keywords
This publication has 34 references indexed in Scilit:
- Increased efficacy of HIV-1 neutralization by antibodies at low CCR5 surface concentrationBiochemical and Biophysical Research Communications, 2006
- CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitroClinical Immunology, 2003
- Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kineticsProceedings of the National Academy of Sciences, 2002
- A biosensor assay for studying ligand-membrane receptor interactions: Binding of antibodies and HIV-1 Env to chemokine receptorsProceedings of the National Academy of Sciences, 2000
- Inhibition of HIV-1 entry before gp41 folds into its fusion-active conformationJournal of Molecular Biology, 2000
- Capture of an early fusion-active conformation of HIV-1 gp41Nature Structural & Molecular Biology, 1998
- The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progressionNature Medicine, 1997
- Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply-Exposed Individuals to HIV-1 InfectionCell, 1996
- HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5Nature, 1996
- Identification of a major co-receptor for primary isolates of HIV-1Nature, 1996