Autocrine nerve growth factor is essential for cell survival and viral maturation in HHV-8-infected primary effusion lymphoma cells.
High levels of nerve growth factor (NGF) are found in sera from individuals infected with human herpesvirus 8 (HHV-8). BC-1 and BCBL-1 cells are primary effusion lymphoma-derived B-cell lines; BC-1 cells are infected by HHV-8 and the Epstein-Barr virus (EBV), and BCBL-1 cells are infected only by HHV-8. Both cells express NGF receptors and produce NGF, whereas RAMOS cells (a B-cell line that is negative for HHV-8 and EBV) express NGF receptors but do not produce detectable NGF. Neutralization of endogenous NGF results in cell growth inhibition and apoptosis in BCBL-1 cells and, to a minor extent, in BC-1 cells. When the HHV-8 lytic cycle is induced in BCBL-1 cells by tetradecanoyl phorbol acetate (TPA), an initial reduction of endogenous NGF production is observed, and many cells undergo apoptosis. However, at 48 hours, TPA-treated cells produce significantly more NGF than untreated controls, and a subsequent recovery of cell viability is observed. Consistent with this finding, the addition of exogenous NGF or anti-NGF antibodies to TPA-treated cells reduces or increases, respectively, the rate of apoptosis in response to TPA. Finally, electron microscopy of TPA-treated BCBL-1 cells shows that the addition of exogenous NGF increases the number of cells producing and releasing complete virions as compared with the controls (25% versus 5%). On the contrary, NGF neutralization leads to the production of defective viral progeny in about 2% of cells. These data indicate that NGF is essential for both cell survival and virus maturation in HHV-8-infected cell lines. (Blood. 2000;95:2905-2912)
Pica
F
F
Departments of Experimental Medicine and Biochemical Sciences, Public Health and Cell Biology, and Neuroscience, University of Rome, Tor Vergata, Rome, Italy. pica@uniroma2.it
Volpi
A
A
Serafino
A
A
Fraschetti
M
M
Franzese
O
O
Garaci
E
E
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D007700:Kinetics; D008223:Lymphoma; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014771:Virion / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D014779:Virus Replication / Q000187:drug effects
D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; D013755:Tetradecanoylphorbol Acetate