DIFFERENTIAL REGULATION OF CXCR4 AND CCR5 ENDOCYTOSIS

The chemokine receptors CCR5 and CXCR4 are major coreceptors/receptors for the CD4-dependent and CD4-independent entry of human and simian i mmunodeficiency viruses. The chemokines that bind and activate these r eceptors can inhibit the entry of viruses that use the respective co-r eceptor molecules. Chemokine-induced coreceptor internalisation is a s ignificant component of the mechanism through which chemokines inhibit virus entry. CXCR4 internalisation is induced by the CXCR4 ligand str omal cell derived factor-1 (SDF-1), phorbol esters and, in T cells, ce llular activation. Here we show that CXCR4 endocytosis can be mediated through either one of two distinct internalisation signals. A COOH-te rminal serine rich domain is required for ligand- but not phorbol este r-induced CXCR4 internalisation. However, a Ser/IleLeu motif, similar to that required for the endocytosis of CD4 and the T cell receptor/CD 3 complex, is required for phorbol ester-induced, but not ligand-induc ed, CXCR4 endocytosis. By contrast, CCR5 internalisation is induced by the beta-chemokine RANTES but not by phorbol esters. CCR5 lacks the S er/IleLeu sequence required for phorbol ester-induced uptake of CXCR4. Together these results indicate that distinct mechanisms can regulate CXCR4 and CCR5 endocytosis and trafficking.