Suppression of dualtropic human immunodeficiency virus type 1 by the CXCR4 antagonist AMD3100 is associated with efficiency of CXCR4 use and baseline virus composition.
In a phase I/II evaluation of the CXCR4 antagonist AMD3100, human immunodeficiency virus RNA levels were significantly reduced in a single study subject who harbored CXCR4 (X4)-tropic virus, but not in subjects who harbored either dual/mixed (DM)-tropic or CCR5 (R5)-tropic virus (C. W. Hendrix et al., J. Acquir. Immune Defic. Syndr. 37:1253-1262, 2004). In this study, we analyzed the envelope clones of DM-tropic virus in baseline and treated virus populations from 14 subjects. Ten subjects exhibited significant reductions in CXCR4-mediated infectivity after 10 days of AMD3100 therapy relative to baseline (X4 suppressor group), while four subjects had no reduction of CXCR4-mediated infectivity (X4 nonsuppressor group). The baseline viruses of the X4 suppressor group infected CXCR4-expressing cells less efficiently than those of the X4 nonsuppressor group. Clonal analysis indicated that the baseline viruses from the X4 suppressor group contained a higher proportion of R5-tropic variants mixed with CXCR4-using variants, while the X4 nonsuppressor group was enriched for CXCR4-using variants. AMD3100 suppressed X4-tropic variants in all subjects studied, but not all dualtropic variants. Furthermore, dualtropic variants that used CXCR4 efficiently were suppressed by AMD3100, while dualtropic variants that used CXCR4 poorly were not. This study demonstrated that AMD3100 has the ability to suppress both X4-tropic and certain dualtropic variants in vivo. The suppression of CXCR4-using variants by AMD3100 is dependent on both the tropism composition of the virus population and the efficiency of CXCR4 usage of individual variants.
Fransen
Signe
S
Monogram Biosciences, South San Francisco, CA 94080, USA.
Bridger
Gary
G
Whitcomb
Jeannette M
JM
Toma
Jonathan
J
Stawiski
Eric
E
Parkin
Neil
N
Petropoulos
Christos J
CJ
Huang
Wei
W
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D014644:Genetic Variation; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D019302:HIV Envelope Protein gp160 / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D012189:Retrospective Studies
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; C059762:HIV envelope protein gp120 (305-321); D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C514797:gp160 protein, Human immunodeficiency virus 1; C088327:plerixafor