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X4 HIV-1 induces neuroblastoma cell death by interference with CXCL12/CXCR4 interaction
S Hatse1, G Bridger, E de Clercq
1Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Sigrid.hatse@rega.kuleuven.ac.be
Abstract:
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.
Insights
Blocking CXC-chemokine receptor 4 (CXCR4) with AMD3100 or X4 HIV-1 inhibits neuroblastoma cell growth. The CXCL12/CXCR4 pathway is crucial for neuroblastoma survival, and its blockade may contribute to HIV-associated neurodegeneration.
Area of Science:
- Neuroscience
- Virology
- Cell Biology
Background:
- Human neuroblastoma SK-N-SH cells express CXC-chemokine receptor 4 (CXCR4) and its ligand CXCL12.
- CXCR4 is a key coreceptor for X4 strains of HIV-1.
Purpose of the Study:
- To investigate the effects of CXCR4 blockade on neuroblastoma cell growth and survival.
- To explore the role of the CXCL12/CXCR4 axis in neuroblastoma cell viability.
- To assess the impact of X4 HIV-1 on neuroblastoma cells.
Main Methods:
- Treatment of SK-N-SH cells with AMD3100 (CXCR4 antagonist) and anti-CXCL12 antibodies.
- Exposure of cells to exogenous CXCL12.
- Incubation of cells with X4 HIV-1 strains (IIIB, SF-2) and an R5 strain (BaL).
- Assessment of cell proliferation, survival, and death.
- Monitoring for HIV production.
Main Results:
- AMD3100 and anti-CXCL12 antibodies inhibited SK-N-SH cell proliferation.
- Exogenous CXCL12 enhanced cell proliferation.
- Prolonged AMD3100 exposure led to cell death due to loss of survival signals.
- X4 HIV-1 strains caused cytopathic effects and cell death, unlike the R5 strain.
- No HIV production was detected in inoculated cultures.
- Exogenous CXCL12 partially protected against X4 HIV-1-induced cell death.
Conclusions:
- The endogenous CXCL12/CXCR4 signaling pathway is essential for neuroblastoma cell survival and proliferation.
- Long-term blockade of CXCR4 by X4 HIV-1 can induce neuronal cell death.
- This mechanism may contribute to neurodegeneration observed in X4 HIV-associated conditions.
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