Susceptibility of diverse primary HIV isolates with varying co-receptor specificity's to CXCR4 antagonistic compounds.

Abstract

The chemokine receptors CCR5 and CXCR4 are an obvious target for HIV therapies. Two compounds, T-22 and AMD-3100, have been shown to inhibit infection of CXCR4-using HIV-1 isolates. The specificity of T-22 and AMD-3100 was further confirmed by their ability to block entry of HIV-1 in GHOST-CXCR4 transfected cells with no effect on viral entry in the GHOST-CCR5 cells. The ability of T-22 to block replication of diverse HIV-1 isolates (group M, subtypes A, B, D, E, and F as well as group O) and HIV-2 primary isolates with varying coreceptor specificities ranging from exclusive CCR5 usage to multiple coreceptor usage was examined in detail. T-22 was found to be highly effective (>90%) at blocking infection of diverse HIV-1 (subtypes A-F, and group O) and HIV-2 isolates that use multiple coreceptors in human PBMCs homozygous for a 32-bp deletion in CCR5 (CCR5-/-), but less effective in CCR5 +/+ PBMCs. Additionally, sequential primary HIV-1 isolates obtained from a longitudinal cohort who had switched from single coreceptor usage to a broad range of multiple receptors could be blocked effectively by both T-22 and AMD-3100 in CCR5-/- PBMCs. Our data suggest that CXCR4 antagonistic compounds are highly effective in blocking the entry of X4-tropic HIV-1, and that these compounds could be a useful additive to current anti-retroviral therapy for clinical management of HIV disease.

• Authors: Sherry M Owen, Donna Rudolph, Dominique Schols, Nobutaka Fujii, Naoki Yamamoto, Renu B Lal
• Journal: Journal of medical virology (J Med Virol) Vol. 68 Issue 2 Pg. 147-55 (Oct 2002) ISSN: 0146-6615 [Print] United States
• PMID: 12210401 (Publication Type: Journal Article)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Anti-HIV Agents
• Benzylamines
• Cyclams
• Heterocyclic Compounds
• Receptors, CCR5
• Receptors, CXCR4
• plerixafor

Topics

• Anti-HIV Agents (pharmacology)
• Benzylamines
• Cell Line
• Cohort Studies
• Cyclams
• Drug Resistance, Viral
• HIV Infections (drug therapy, physiopathology, virology)
• HIV-1 (drug effects, isolation & purification, pathogenicity, physiology)
• HIV-2 (drug effects, isolation & purification, pathogenicity, physiology)
• Heterocyclic Compounds (pharmacology)
• Humans
• In Vitro Techniques
• Longitudinal Studies
• Receptors, CCR5 (deficiency, genetics, physiology)
• Receptors, CXCR4 (antagonists & inhibitors)