X4 HIV-1 induces neuroblastoma cell death by interference with CXCL12/CXCR4 interaction.
Human neuroblastoma SK-N-SH cells strongly express CXC-chemokine receptor 4 (CXCR4), the principal coreceptor for X4 HIV-1 strains, and its natural ligand stromal cell-derived factor 1 (SDF-1, recently renamed CXCL12). We investigated the impact of CXCR4 blockade by the specific CXCR4 antagonist AMD3100 or by X4 HIV-1 virus particles on the growth and survival of neuroblastoma SK-N-SH cells. SK-N-SH cell proliferation was inhibited byAMD3100 and anti-CXCL12 neutralizing antibodies, but enhanced by exogenously added CXCL12. Upon prolongedexposure to AMD3100, SK-N-SH cell death occurred throughdeficit of survival-promoting and growth-stimulatory signals generated by endogenous CXCL12. In analogy with the observations made with the CXCR4 inhibitor AMD3100, the X4 HIV-1 strains IIIB and SF-2, but not the R5 strain BaL, caused a marked cytopathic effect and strongly effected SK-N-SH cell death after at least 10 days of incubation. However, no virus production could be detected in the HIV-1-inoculated SK-N-SH cell cultures. Exogenously added CXCL12 afforded partial protection against X4 HIV-1-induced cytopathicity in SK-N-SH cells. Our data indicate that the endogenous CXCL12/CXCR4 signaling axis is critical for neuroblastoma cell survival and proliferation. Long-term blockade of CXCR4 through physical contact with the X4 HIV-1 envelope can cause neuronal cell death. This mechanism may possibly play a role in X4 HIV-associated neurodegeneration.
Hatse
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Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Sigrid.hatse@rega.kuleuven.ac.be
Bridger
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G
de Clercq
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Schols
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D001254:Astrocytoma / Q000235:genetics; D001596:Benzylamines; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000080027:Cyclams; D003588:Cytopathogenic Effect, Viral; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008024:Ligands; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C088327:plerixafor