Cellular homologues

Herpesviruses provide examples of viral piracy of host genes, which may play roles in immune evasion. HHV-6 encodes several chemokine and chemokine receptor homologues (Isegawa et al., 1998; Menotti et al., 1999; Zou et al., 1999; Milne et al., 2000; Bradel-Tretheway et al., 2003; Luttichau et al., 2003).

U83 encodes a functional chemokine (Zou et al., 1999). Although the gene has relatively little sequence similarity to human chemokine genes, the protein expressed has the typical cysteine residues of a chemokine, transduces signals that involve calcium fluxes and induces chemotactic activation. The recombinant U83 protein is capable of inducing transient calcium mobilization in THP-1 cells and of chemotactically activating THP-1 cells (Zou et al., 1999). Furthermore, the U83 has been found to cause calcium mobilization as efficiently through the CCR2 receptor (Luttichau et al., 2003), suggesting that the U83 protein might play an important role in HHV-6 propagation in vivo by activating and trafficking mononuclear cells to sites of viral replication, or U83 during reactivation of the virus in for example monocyte-derived microglia could perhaps be involved in the pathogenesis of the CCR2-dependent disease, multiple sclerosis.

HHV-6 contains two genes, U12 and U51 that encode putative homologues of cellular G-protein-coupled receptors (GCR). The U12 gene is expressed late in infection from a spliced mRNA. U12 functionally encoded a calcium-mobilizing receptor for beta-chemokines such as regulated upon activation, normal T expressed and secreted (RANTES), macrophage inflammatory proteins 1a and 1b (MIP-1a and MIP-1b) and monocyte chemoattractant protein 1, but not for the a-chemokine interleukin-8, suggesting that the chemokine selectivity of the U12 product is distinct from that of the known mammalian chemokine receptors (Isegawa et al., 1998).

U51 gene defines a new family of betaherpesvirus-specific genes encoding multiple transmembrane glycoproteins with similarity to G protein-coupled receptors, in particular, human chemokine receptors. When synthesized in transient expression systems, U51 intracellular trafficking is regulated in a cell-type-dependent fashion. In human monolayer HEK-293 and 143tk— cells, U51 accumulates predominantly in the endoplasmic reticulum and fails to be transported to the cell surface. In contrast, in T-lymphocytic cell lines J-Jhan, Molt-3 and Jurkat, U51 is successfully transported to the plasma membrane. The transport of U51 to the cell surface requires a cell-specific function present in activated T lymphocytes and T-cell lines (Menotti et al., 1999).

On the other hand, U51 stably expressed in cell lines shows specific binding of the CC chemokine RANTES and competitive binding with other beta chemokines, such as eotaxin; monocyte chemoattractant proteins 1, 3 and 4; as well as the HHV-8 chemokine vMIPII. In epithelial cells already secreting RANTES, U51 expression induces specific transcriptional downregulation of RANTES (Milne et al., 2000).

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