V3-independent competitive resistance of a dual-X4 HIV-1 to the CXCR4 inhibitor AMD3100

PLoS One. 2014 Feb 19;9(2):e89515. doi: 10.1371/journal.pone.0089515. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Benzylamines
  • Cloning, Molecular
  • Cyclams
  • Drug Resistance, Viral / genetics*
  • Evolution, Molecular*
  • HIV-1 / genetics*
  • Heterocyclic Compounds / pharmacology*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Sequence Analysis, Protein
  • Virus Internalization

Substances

  • Benzylamines
  • Cyclams
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • plerixafor

Grants and funding

This work was supported by a Joint Research Grant from the Institute of Tropical Medicine, Nagasaki University, and the Global COE program “Global Education and Research Center Aiming at the control of AIDS” supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.