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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2905-2912
Autocrine nerve growth factor is essential for cell survival and
viral maturation in HHV-8-infected primary effusion lymphoma cells
Francesca Pica,
Antonio Volpi,
Annalucia Serafino,
Marzia Fraschetti,
Ornella Franzese, and
Enrico Garaci
From the Departments of Experimental Medicine and Biochemical
Sciences, Public Health and Cell Biology, and Neuroscience,
University of Rome, Tor Vergata, Rome, Italy, and The
Institute of Experimental Medicine, Consiglio Nazionale
della Ricerche (National Research Council), Rome, Italy.
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.
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