Syncytium formation amplifies apoptotic signals: a new view on apoptosis in HIV infection in vitro

Infection of CD4+ cells with HIV in vitro causes extensive cytopathology. The mechanism that underlies this process is unclear and conflicting data exist regarding whether cytotoxicity is due to necrosis or apoptosis. It was previously reported and is shown here that the coculture of HIV glycoprotein-expressing cells with CD4+ cells results in apoptosis within several hours. This study demonstrates that apoptosis did not occur in single cells and was mediated neither by CD4 nor by coreceptor signaling, indicating that apoptosis was not induced by intra- or intercellular glycoprotein-receptor interaction. Detection of apoptosis required cell-to-cell fusion and undetectable levels of apoptotic cell death were substantially amplified upon syncytium formation. Similar results were obtained with syncytium-forming cultures of measles virus glycoprotein-expressing cells. These findings indicate that the apoptotic cell death observed in cultures of HIV and other syncytium-forming viruses is primarily due to amplification of background apoptosis in the wake of cell-to-cell fusion.