title: V3-independent competitive resistance of a dual-X4 HIV-1 to the CXCR4 inhibitor AMD3100.
abstract: A CXCR4 inhibitor-resistant HIV-1 was isolated from a dual-X4 HIV-1 in vitro. The resistant variant displayed competitive resistance to the CXCR4 inhibitor AMD3100, indicating that the resistant variant had a higher affinity for CXCR4 than that of the wild-type HIV-1. Amino acid sequence analyses revealed that the resistant variant harbored amino acid substitutions in the V2, C2, and C4 regions, but no remarkable changes in the V3 loop. Site-directed mutagenesis confirmed that the changes in the C2 and C4 regions were principally involved in the reduced sensitivity to AMD3100. Furthermore, the change in the C4 region was associated with increased sensitivity to soluble CD4, and profoundly enhanced the entry efficiency of the virus. Therefore, it is likely that the resistant variant acquired the higher affinity for CD4/CXCR4 by the changes in non-V3 regions. Taken together, a CXCR4 inhibitor-resistant HIV-1 can evolve using a non-V3 pathway.
authors.affiliation: Department of Medical Virology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Medical Virology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Terasawa
authors.affiliation: Department of Medical Virology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Department of Medical Virology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Monde
authors.affiliation: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yusa
authors.affiliation: AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.affiliation: Department of Medical Virology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Harada
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001596:Benzylamines; D003001:Cloning, Molecular; D000080027:Cyclams; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D015497:HIV-1 / Q000235:genetics*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D020539:Sequence Analysis, Protein; D053586:Virus Internalization
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor