Susceptibility of diverse primary HIV isolates with varying co-receptor specificity's to CXCR4 antagonistic compounds.
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.
Owen
Sherry M
SM
HIV Immunology and Diagnostic Branch, Division of AIDS, STD, and TB, Centers for Disease Control and Prevention, Public Health Services, U.S. Department of Health and Human Services, Atlanta, Georgia, USA.
Rudolph
Donna
D
Schols
Dominique
D
Fujii
Nobutaka
N
Yamamoto
Naoki
N
Lal
Renu B
RB
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D002460:Cell Line; D015331:Cohort Studies; D000080027:Cyclams; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D015498:HIV-2 / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008137:Longitudinal Studies; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C088327:plerixafor