The cytopathic effects (CPE) resulting from the infection of CD4+ T cells by human herpes-virus 7 (HHV-7) comprises two major mechanisms: generation of large polyploid cells, which eventually undergo necrotic lysis, and apoptosis, predominantly occurring in small mononucleated cells. To dissect the relative contribution of these two phenomena to the overall cytopathicity of HHV-7 in vitro, we have investigated the effect of acute HHV-7 infection on SupT1 CD4+ T cell lines stably transfected either with the bcl-2 anti-apoptotic gene or with the control vector. Overexpression of Bcl-2 protein by these cells was associated with a progressive decline of the total number of viable cells, and a relative increase of enlarged polyploid cell. Of note, the size of polyploid cells was significantly greater in SupT1 cells overexpressing bcl-2 than in cells transfected with the control vector. In addition, bcl-2 expression accelerated the kinetics of an acute spreading of HHV-7 infection, as determined by HHV-7-specific indirect immunostaining revealed by either fluorescence microscopy or flow cytometry. Our results indicate that inhibition of apoptosis in HHV-7-infected cultures greatly favors the process of polyploidization and represents a major mechanism to maximize viral transmission.