Sindbis virus is an alphavirus that is transmitted by mosquitoes to animal and human hosts in manygeographical locations worldwide. Sindbis virus is a relatively mild human pathogen but causes mild to severe encephalitis and mortality in mice, thereby serving as a model for related human encephalitic viruses. Our laboratory has extended the use of Sindbis virus as a tool to study the role of programmed cell death in a variety of human disorders. We found that Sindbis virus infects and induces classic apoptotic cell death in a variety of cultured cell lines and in cultured primary neurons. Despite its broad tropism in cell culture, sindbis virus is profoundly neuronotropic in the brains and spinal cords of mice. Sindbis virus also induces apoptosisof neurons in mice, with young mice being generally more susceptible to neuronal apoptosis and fatal infections than older mice. The mechanisms by which some neurons resist Sindbis virus-induced apoptosis to produce a persistent virus infection is not understood. Similarly, it is not understood why mosquitoes and mosquito cell lines often fail to under go programmed cell death upon infection with Sindbis virus. To study cellular genes that modulate the outcome of a Sindbis virus infection in vivo, we converted Sindbis virus into a vector by inserting a cassette into the viral genome. This cassette contains a duplicated copy of the Sindbis virus subgenomic promoter to drive expression of proteins of interest. This virus vector, together with knockout mice, has allowed us to study the role of pro-apoptotic Bcl-2 family proteins Bax and Bak in modulating the outcome of a Sindbis virus infection. This work led to the unexpected finding that Baxand Bak can function as potent inhibitors of neuronal apoptosis in mice. We now support the hypothesis that Bak and perhaps Bax as well inhibits synaptic activity by regulating mitochondrial function, thereby protecting neurons and mice from Sindbis virus-induced excitotoxic neuronal damage.