CD4-INDEPENDENT ASSOCIATION BETWEEN HIV-1 GP120 AND CXCR4 - FUNCTIONAL CHEMOKINE RECEPTORS ARE EXPRESSED IN HUMAN NEURONS

Background: Chemokines are a family of proteins that chemoattract and activate immune cells by interacting with specific receptors on the su rface of their targets. We have shown previously that chemokine recept ors including the interleukin-8 receptor B (CXCR2) and the Duffy blood group antigen are expressed on subsets of neurons in Various regions of the adult central nervous system. Results: Using a combination of i mmunohistochemical staining and receptor-binding studies, we show that hNT cells, which are differentiated human neurons derived from the ce ll line NTera 2, express functional chemokine receptors of the C-X-C a nd C-C types. These chemokine receptors include CXCR2, CXCR4, CCR1 and CCR5. We demonstrate high-affinity binding of both types of chemokine s to hNT neurons and dose-dependent chemotactic responses to these che mokines in differentiated, but not undifferentiated, NTera 2 cells, In addition, we show that the envelope glycoprotein from the T-cell-trop ic human immunodeficiency virus 1 (HIV-1) strain IIIB is a CD4-indepen dent, dose-dependent inhibitor of the binding of stromal cell-derived factor 1 to its receptor, CXCR4. Conclusions: These data support the r ecent findings that members of the chemokine receptor family, includin g CCR5 and LESTR/Fusin (CXCR4), function as coreceptors in combination with CD4 for HIV-1 invasion. This is the first report of functional e xpression of chemokine receptors on human neurons. Furthermore, our st udies provide evidence for the direct, CD4-independent association of the viral envelope protein of the HIV-1 strain IIIB with the chemokine receptor CXCR4.