In vitro cytobiological effects of human herpesviruses 6 and 7: immunohistological monitoring of apoptosis, differentiation and cell proliferation.

Two human herpesviruses, HHV-6 and HHV-7, recently identified and closely related, were studied for their influence on cellular apoptosis and proliferation. Infection was monitored by viral DNA--and antigen expression. Apoptosis and cell proliferation were determined by immunocytological techniques and the markers p53, p21WAF/Cip, Bax, Bak, Bcl-2, cyclin D1 and PCNA, and also screened for signal transduction indicators such as c-H-ras, c-fos and raf-1. Cell differentiation and function was monitored by determining cell membrane receptors including Fas and CD specificities, and by ELISA tests for interleukin production. Both HHV-6 and HHV-7 readily infected their target cells, yet virus antigen expression and virus replication were less active in HHV-7 infection. Both viruses also induced GM-CFS production. Cell differentiation in terms of CD receptor expression was more pronounced in HHV-6 than in HHV-7 infection. No differences were found in the activity of signal transduction factors. There were quantitative differences in the activation of p53, Bax, p21WAF and Bcl-2 in HHV 6-infected CBC as compared to HHV-7 infection supporting the apoptosis cycle. CyclinD1 activity remained at lower levels in HHV-7 infected CBC, yet was high in similarly infected transformed SupT1 cells. In contrast, HHV-6 supported rather the p53/p21WAF apoptosis pathway in both untransformed CBC and transformed HSB1 cells. Both herpesviruses, HHV-6 and HHV-7, thus possessed similar biological activities in cultures of non-transformed susceptible cells, although with certain quantitative differences. The data reported here may further support the notion that HHV-7 is less active in inducing apoptosis thus favoring continued cell proliferation. The mechanism by which these viruses interfere with the network control of cell proliferation, differentiation and apoptosis appear more complicated than shown here and therefore afford a more detailed study, including a more sensitive technology than immunohistology.