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Abstract
QST-DIH -RANTES: A NOVEL CCR5 LIGAND WITH POTENT ANTI-HIV ACTIVITY
PICCHIO G, PASTORE C, GALIMI F, CHALOIN O, HARTLEY O, OFFORD R, MOSIER D
BACKGROUND: Prevention of HIV-1 entry into target cells by amino-terminal modified CCR5 ligands is an attractive potential therapeutic approach. In this study, we report on CCR5 internalization and anti-HIV-1 activity of QST-DIH-RANTES, a new member of this family of compounds. METHODS: NNY- and QST-DIH-RANTES IC50 were determined for HIV-1 BaL (R5), and HIV-1 AB-28 (R5) using CD4+.CCR5+.U87 cells, and 2 clones of MT-2 cells expressing different stable levels of CCR5 (difference > 1log). Down -modulation and re-expression rates of CCR5 upon exposure to NNY- or QST-DIH-RANTES were determined by flow cytometry using primary activated CD4+ T-cells from CCR5 homozygous wild type, and CCR5 delta32 heterozygous donors (J.Virol. 75:661, 2001). RESULTS: On average, NNY-RANTES IC50 for both HIV-1 isolates studied was 1 log higher than for QST-DIH (NNY-RANTES mean IC50=7.08 nM (range 6.45-7.71 nM) vs. QST-DIH-RANTES mean IC50=0.53 nM (range 0.413-0.66 nM)). QST-DIH-RANTES IC50 was dependent on the CCR5 level expressed by the target cell. The IC50 for HIV-1 BaL on MT-2 expressing high levels of CCR5 was 7.5 nM vs. 0.9 nM for MT-2 cells expressing intermediate levels of CCR5. The rate of CCR5 down-modulation observed with both compounds and CCR5 genotypes studied was similar. In contrast, QST-DIH-RANTES significantly delayed reexpression of CCR5 (75% control CCR5 index) measured at 24 hrs. after compound removal in comparison to NNY-RANTES (100%). This effect was more pronounced in CD4+ T-cells from CCR5 delta32 heterozygous donors (QST-DIH-RANTES=5% control CCR5 index vs. NNY-RANTES=40% CCR5 control index). CONCLUSIONS: QST-DIH-RANTES is a novel modified CCR5 ligand with better anti-HIV activity than the previously characterized NNY-RANTES. Cell surface CCR5 levels influence the potency of this compound. The delayed reexpression of CCR5 observed after brief exposure to QST-DIH-RANTES may explain the improved anti-viral activity compared to NNY-RANTES.
The 1st. IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
71
Suggested Citation
"PICCHIOG, et al.
QST-DIH -RANTES: A NOVEL CCR5 LIGAND WITH POTENT ANTI-HIV ACTIVITY.
Oral Presentation:
The 1st. IAS Conference on HIV Pathogenesis and Treatment
:
Abstract no.
71"
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