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 surface of their targets. We have shown previously that chemokine receptors 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 nervous system.


RESULTS
Using a combination of immunohistochemical staining and receptor binding studies, we show that hNT cells, which are differentiated human neurons derived from the cell line NTera2, express functional chemokine receptors of the C-X-X and C-C types. These chemokine receptors include CXCR2, CXCR4, CCR1 and CCR5. We demonstrate high-affinity binding of both types of chemokines to hNT neurons and dose-dependent chemotactic responses to these chemokines in differentiated, but no t undifferentiated, NTera 2 cells. In addition, we show that the envelop glycoprotein from the T-cell-tropic human immunodeficiency virus 1 (HIV-1) strain IIIB is a CD4-independent, dose-dependent inhibitor of the binding of stromal cell-derived factor 1 to its receptor, CXCR4.


CONCLUSIONS
These data support recent findings that members of the chemokine family, including CCR5 and LESTR/Fusin (CXCR4), function as coreceptors in combination with CD4 for HIV-1 invasion. This is the first report of functional expression of chemokine receptors on human neurons. Furthermore, our studies provide for direct CD4-independent association of the viral envelope protein of the HIV-1 strain III with the chemokine receptor CXCR4.
Hesselgesser
J
J
Department of Immunology, Berlex Biosciences, Richmond, California 94804, USA. Joe_Hesselgesser@berlex.com
Halks-Miller
M
M
DelVecchio
V
V
Peiper
S C
SC
Hoxie
J
J
Kolson
D L
DL
Taub
D
D
Horuk
R
R
D000328:Adult; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000502:physiology*; D015704:CD4 Antigens / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism / Q000494:pharmacology*; D019743:Chemokines, CXC; D002633:Chemotaxis; D006224:Cricetinae; D005333:Fetus; D019204:GTP-Binding Proteins / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology*; D009474:Neurons / Q000276:immunology / Q000502:physiology*; D019718:Receptors, CXCR4; D015728:Receptors, HIV / Q000096:biosynthesis / Q000502:physiology*
D015704:CD4 Antigens; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D019204:GTP-Binding Proteins