CXC-Chemokine Receptor 4 Is Not a Coreceptor for Human Herpesvirus 7 Entry into CD4(+) T Cells

Human herpesvirus 7 (HHV-7) is a T-lymphotropic virus which utilizes the CD4 receptor as its main receptor to enter the target cells. Hence, HHV-7 can interfere with human immunodeficiency virus type 1 (HIV-1) infection in CD4(+) T cells. It was recently suggested that the CXC chemokine receptor 4 (CXCR4), which was found to be a crucial coreceptor for T-tropic HIV-1 strains, may also play a role in the HHV-7 infection process. However, the results presented here demonstrate that CXCR4 is not involved in HHV-7 infection. The natural ligand of CXCR4, SDF-1α, was not able to inhibit HHV-7 infection in SupT1 cells or in CD8(+) T-cell-depleted peripheral blood mononuclear cells. Also, AMD3100, a specific CXCR4 antagonist with potent antiviral activity against T-tropic HIV strains (50% inhibitory concentration [IC(50)], 1 to 10 ng/ml), completely failed to inhibit HHV-7 infection (IC(50), >250 μg/ml). Thus, two different agents known to specifically interact with CXCR4 were not able to inhibit HHV-7 infection. Other T-lymphoid cell lines, expressing both CD4 and CXCR4 (e.g., HUT-78 and MT-4) could not be infected by HHV-7. In addition, the CD4-transfected cell lines HOS.CD4 and U87.CD4 and the CD4/CXCR4 double-transfected cell lines HOS.CD4.CXCR4 and U87.CD4.CXCR4 were not infectable with HHV-7. Also, we found no down-regulation of surface-bound or intracellular CXCR4 in HHV-7-infected CD4(+) T cells. As compared to uninfected SupT1 cells, stromal cell-derived factor 1α (SDF-1α)/CXCR4-mediated intracellular calcium flux was unchanged in SupT1 cells that were acutely or persistently infected with HHV-7. All these data argue against CXCR4 as a receptor involved in the HHV-7 infection process.

人类疱疹病毒7型（Human herpesvirus 7, HHV-7）是一种嗜T淋巴细胞病毒，以CD4受体作为主要受体侵入靶细胞。因此，HHV-7可在CD4阳性T细胞中干扰人类免疫缺陷病毒1型（Human immunodeficiency virus type 1, HIV-1）的感染过程。近期有研究提出，CXC趋化因子受体4（CXC chemokine receptor 4, CXCR4）——作为嗜T细胞型HIV-1毒株的关键共受体——可能也参与了HHV-7的感染过程。但本文呈现的实验结果表明，CXCR4并未参与HHV-7的感染。CXCR4的天然配体基质细胞衍生因子1α（stromal cell-derived factor 1α, SDF-1α），无法抑制SupT1细胞以及去除CD8阳性T细胞的外周血单个核细胞中的HHV-7感染。此外，AMD3100——一种对嗜T细胞型HIV毒株具有强效抗病毒活性的特异性CXCR4拮抗剂，其50%抑制浓度（IC₅₀）为1~10 ng/ml——完全无法抑制HHV-7的感染（IC₅₀>250 μg/ml）。由此可见，两种已知可特异性结合CXCR4的试剂均未能抑制HHV-7的感染。其他同时表达CD4与CXCR4的T淋巴细胞系（如HUT-78与MT-4）也无法被HHV-7感染。此外，转染CD4的细胞系HOS.CD4、U87.CD4，以及共转染CD4与CXCR4的细胞系HOS.CD4.CXCR4、U87.CD4.CXCR4，均不能被HHV-7感染。我们还发现，在HHV-7感染的CD4阳性T细胞中，膜结合型或胞内型CXCR4均未出现表达下调。与未感染的SupT1细胞相比，急性感染或持续感染HHV-7的SupT1细胞中，基质细胞衍生因子1α（stromal cell-derived factor 1α, SDF-1α）/CXCR4介导的细胞内钙流未发生改变。上述所有实验结果均不支持CXCR4作为受体参与HHV-7的感染过程。