The Cytomegalovirus-Encoded Chemokine Receptor US28 Can Enhance Cell-Cell Fusion Mediated by Different Viral Proteins

The human cytomegalovirus (CMV) US28 gene encodes a functional CC chemokine receptor. However, this activity was observed in cells transfected to express US28 and might not correspond to the actual role of the protein in the CMV life cycle. Expression of US28 allows human immunodeficiency virus type 1 (HIV-1) entry into certain CD4(+) cells and their fusion with cells expressing HIV-1 envelope (Env) proteins. Such properties were initially reported for the cellular chemokine receptors CCR5 and CXCR4, which behave as CD4-associated HIV-1 coreceptors. We found that coexpression of US28 and either CXCR4 or CCR5 in CD4(+) cells resulted in enhanced synctium formation with HIV-1 Env(+) cells. This positive effect of US28 on cell fusion seems to be distinct from its HIV-1 coreceptor activity. Indeed, enhancement of cell fusion was also observed when US28 was expressed on the HIV-1 Env(+) cells instead of an CD4(+) target cells. Furthermore, US28 could enhance cell fusion mediated by other viral proteins, in particular, the G protein of vesicular stomatitis virus (VSV-G). The HIV-1 coreceptor and fusion-enhancing activities could be affected by mutations in different domains of US28. The fusion-enhancing activity of US28 seems to be cell type dependent. Indeed, cells coexpressing VSV-G and US28 fused more efficiently with human, simian, or feline target cells, while US28 had no apparent effect on fusion with the three mouse or rat cell lines tested. The positive effect of US28 on cell fusion might therefore require its interaction with a cell-specific factor. We discuss a possible role for US28 in the fusion of the CMV envelope with target cells and CMV entry.

人类巨细胞病毒（human cytomegalovirus, CMV）US28基因编码一种功能性CC趋化因子受体（CC chemokine receptor）。然而，该活性仅在经转染表达US28的细胞中被观测到，未必与该蛋白在CMV生命周期中的实际功能相符。US28的表达可使人类免疫缺陷病毒1型（human immunodeficiency virus type 1, HIV-1）入侵部分CD4阳性细胞，并介导其与表达HIV-1包膜（envelope, Env）蛋白的细胞发生融合。这类特性最初曾在细胞趋化因子受体CCR5与CXCR4中被报道，二者可作为CD4相关的HIV-1共受体。本研究发现，在CD4阳性细胞中共表达US28与CXCR4或CCR5，可使其与表达HIV-1 Env的细胞发生更显著的合胞体形成。US28对细胞融合的这种促进效应，似乎与其作为HIV-1共受体的活性有所区别。事实上，当US28在表达HIV-1 Env的细胞中表达，而非在CD4阳性靶细胞中表达时，同样可观测到细胞融合的增强效应。此外，US28还可增强其他病毒蛋白介导的细胞融合，尤其是水疱性口炎病毒（vesicular stomatitis virus, VSV-G）的G蛋白。US28的HIV-1共受体活性与融合增强活性，可被其不同结构域的突变所影响。US28的融合增强活性似乎具有细胞类型依赖性。事实上，共表达VSV-G与US28的细胞，可更高效地与人类、猴类或猫科来源的靶细胞发生融合；而US28对三种小鼠或大鼠细胞系的融合过程无显著影响。因此，US28对细胞融合的促进效应，可能需要其与细胞特异性因子发生相互作用。本研究还讨论了US28在CMV包膜与靶细胞融合以及CMV入侵过程中可能发挥的作用。