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.
Highlights
The entry of human immunodeficiency virus type 1 (HIV-1) is initiated by an interaction of viral envelope glycoprotein gp120 with the principal receptor CD4 and one of the coreceptors, either CCR5 or CXCR4, expressed in the target cells
Characterization of CXCR4 inhibitor-resistant HIV-1 is important to understand how the virus can escape from inhibitors targeting coreceptors clinical application of CXCR4 inhibitors for treatment of HIV-1-infected individuals remains a matter of debate
The V3 loop is a crucial determinant for coreceptor selectivity and resistance to coreceptor inhibitors and natural ligands
Summary
The entry of human immunodeficiency virus type 1 (HIV-1) is initiated by an interaction of viral envelope glycoprotein gp120 with the principal receptor CD4 and one of the coreceptors, either CCR5 or CXCR4, expressed in the target cells. SDF-1a (a natural ligand for CXCR4) and CXCR4 inhibitors such as AMD3100 and T134 induce selection of inhibitor-resistant variants among X4 viruses without changing coreceptor usage [24,25,26,27,28,29] These resistant variants contain various mutations in multiple regions of gp120, the majority of mutations accumulate in the V3 loop, and some of these mutations are shared in different resistant variants. The reversion is associated with substitution in the 11th position of the V3 loop from arginine to serine [30], which is consistent with the 11/25th rule It remains elusive how coreceptor inhibitors induce evolution of HIV-1 to use different coreceptors or acquire resistance. We selected AMD3100-escape variants from a dual-X4 HIV-1 carrying the V3 loop from CRF01_AE, which has no positively charged amino acids at the 11th or 25th positions and lacks an Nlinked glycan in the V3 loop, to elucidate HIV-1 evolution for escape from CXCR4 inhibitors
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