Esté J A, Cabrera C, Blanco J, Gutierrez A, Bridger G, Henson G, Clotet B, Schols D, De Clercq E
Institut de Recerca de la SIDA-Caixa, Retrovirology Laboratory, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.
J Virol. 1999 Jul;73(7):5577-85. doi: 10.1128/JVI.73.7.5577-5585.1999.
The emergence of X4 human immunodeficiency virus type 1 (HIV-1) strains in HIV-1-infected individuals has been associated with CD4(+) T-cell depletion, HIV-mediated CD8(+) cell apoptosis, and an impaired humoral response. The bicyclam AMD3100, a selective antagonist of CXCR4, selected for the outgrowth of R5 virus after cultivation of mixtures of the laboratory-adapted R5 (BaL) and X4 (NL4-3) HIV strains in the presence of the compound. The addition of AMD3100 to peripheral blood mononuclear cells infected with X4 or R5X4 clinical HIV isolates displaying the syncytium-inducing phenotype resulted in a complete suppression of X4 variants and a concomitant genotypic change in the V2 and V3 loops of the envelope gp120 glycoprotein. The recovered viruses corresponded genotypically and phenotypically to R5 variants in that they could no longer use CXCR4 as coreceptor or induce syncytium formation in MT-2 cells. Furthermore, the phenotype and genotype of a cloned R5 HIV-1 virus converted to those of the R5X4 virus after prolonged culture in lymphoid cells. However, these changes did not occur when the infected cells were cultured in the presence of AMD3100, despite low levels of virus replication. Our findings indicate that selective blockade of the CXCR4 receptor prevents the switch from the less pathogenic R5 HIV to the more pathogenic X4 HIV strains, a process that heralds the onset of AIDS. In this article, we show that it could be possible to redirect the evolution of HIV so as to impede the emergence of X4 strains or to change the phenotype of already-existing X4 isolates to R5.
在人类免疫缺陷病毒1型（HIV-1）感染者中出现的X4型HIV-1毒株与CD4(+) T细胞耗竭、HIV介导的CD8(+)细胞凋亡以及体液免疫反应受损有关。双环胺AMD3100是CXCR4的选择性拮抗剂，在该化合物存在的情况下，对实验室适应的R5（BaL）和X4（NL4-3）HIV毒株混合物进行培养后，其选择了R5病毒的生长。将AMD3100添加到感染了表现出合胞体诱导表型的X4或R5X4临床HIV分离株的外周血单个核细胞中，导致X4变体完全被抑制，同时包膜糖蛋白gp120的V2和V3环发生基因型改变。回收的病毒在基因型和表型上与R5变体相对应，因为它们不再能将CXCR4用作共受体，也不能在MT-2细胞中诱导合胞体形成。此外，克隆的R5 HIV-1病毒在淋巴细胞中长时间培养后，其表型和基因型转变为R5X4病毒的表型和基因型。然而，尽管病毒复制水平较低，但在AMD3100存在的情况下培养感染细胞时，这些变化并未发生。我们的研究结果表明，CXCR4受体的选择性阻断可防止从致病性较低的R5 HIV向致病性较高的X4 HIV毒株的转变，这一过程预示着艾滋病的开始。在本文中，我们表明有可能改变HIV的进化方向，以阻止X4毒株的出现，或将已有的X4分离株的表型转变为R5。
