PROMISCUOUS USE OF CC AND CXC CHEMOKINE RECEPTORS IN CELL-TO-CELL FUSION MEDIATED BY A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-2 ENVELOPE PROTEIN

The CC chemokine receptors CCR5, CCR2, and CCR3 and the CXC chemokine receptor CXCR4 have been implicated as CD4-associated cofactors in the entry of primary and cell line-adapted human immunodeficiency virus t ype 1 (HIV-1) strains. CXCR4 is also a receptor for T-cell-line-adapte d, CD4-independent strains of HIV-2. With the exception of this latter example, little has been reported on the entry cofactors used by HIV- 2 strains. Here we show that a CD4-dependent, T cell-line-adapted HIV- 2 strain uses CXCR4 and, to a lesser extent, CCR3 for fusion with and infectious entry into cells. In a cell-to-cell fusion assay, the envel ope protein of this virus can utilize a wider repertoire of chemokine receptors to induce fusion. These include CCR1, CCR2, CCR3, CCR4, CCR5 , CXCR2, and CXCR4. Kinetic analysis indicated that cell lines express ing the receptors that support infection, CXCR4 and CCR3, form syncyti a more rapidly than do cell lines expressing the other receptors. Neve rtheless, although less efficient, fusion with CXCR2 expressing cells was specific, since it was inhibited by antibodies against CXCR2. The extensive use of chemokine receptors in cell-to-cell fusion has implic ations for understanding the molecular basis of CD4-chemokine receptor -induced lentivirus fusion and may have relevance for syncytium format ion and the direct cell-to-cell transfer of virus in vivo.