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American Journal of Pathology, Vol 149, 1531-1539, Copyright © 1996 by American Society for Investigative Pathology
REGULAR ARTICLES |
A Kovacs, ML Weber, LJ Burns, HS Jacob and GM Vercellotti
Department of Medicine, University of Minnesota, Minneapolis, USA.
Human umbilical vein endothelial cells were infected with human cytomegalovirus (HCMV) at a multiplicity of infection of 0.1 plaque- forming unit/cell and remained > 95% viable even after 10 days of infection. To induce apoptosis, control human umbilical vein endothelial cells and cells infected with HCMV for 3, 5, and 7 days were serum starved for 48 hours. Almost one-half of the uninfected cells lost viability after 48 hours of serum starvation whereas HCMV- infected cells were virtually unaffected (< 20% death, P < 0.05). Uninfected cells showed typical hallmarks of apoptosis, including unique morphological changes and DNA laddering. HCMV-infected cells, concomitant with their resistance to serum-starvation-induced death, displayed almost none of these characteristics. Active replication of HCMV was necessary for the anti-apoptotic effect, as cells treated with ultraviolet light-inactivated virus were not protected. p53, the G1/S phase cell cycle brake protein, was elevated in HCMV-infected cells. However, rather than accumulating in the nucleus, immunofluorescent and Western blot studies demonstrated remarkable and predominant cytoplasmic sequestration of p53 in HCMV-infected endothelial cells. Although HCMV proteins have already been shown to block apoptosis, we suggest that the aberrant subcellular pattern of p53 is the disturbed cellular mechanism that may be responsible for the anti-apototic properties of HCMV-infected cells. The selective resistance to apoptosis can be important during HCMV replication and may explain the oncogenic potential of HCMV as well as its pathogenic role in intimal- proliferation-mediated vascular diseases.
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