Many reports have indicated that infection with SV or SFV induces apoptosis both in cultured cells and in the CNS of mice. In general, the ability of virus strains to induce apoptosis correlates with their neurovirulence, although both apoptosis and neurovirulence are age dependent, i.e., resistance increases with age. SV can induce apoptosis simply by the process of membrane fusion and entry, by the expression of the envelope proteins, or by the expression of the nonstructural protein, nsP2. However, viral particles are not necessary to activate apoptosis, since transfection with viral RNA or even viral RNA expressing only the nonstructural proteins will result in apoptosis. The cellular pathways involved in alphavirus-induced apoptosis are complex, and much remains poorly understood. Experimental results point to the involvement of both the mitochondrial and the death receptor pathways. To date, there are no reports implicating the ER stress pathway.