This study identifies Beclin, a novel Bcl-2-interacting protein, as a potential antiviral host defense molecule that protects against fatal Sindbis virus encephalitis. Bcl-2, a well-known antiapoptotic protein, was previously shown to reduce Sindbis virus replication and prevent virus-induced apoptosis in mouse brains, thereby protecting against lethal encephalitis. Using a yeast two-hybrid screen, researchers identified Beclin, a 60-kDa coiled-coil protein that interacts with Bcl-2 in mammalian cells. Recombinant Sindbis viruses expressing full-length human Beclin (SIN/beclin) showed significantly higher survival rates in infected mice compared to viruses expressing Beclin lacking the Bcl-2-binding domain (SIN/beclin ΔBcl-2BD) or Beclin with a premature stop codon (SIN/beclinstop). Mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than those infected with the other viruses. These findings suggest that Beclin plays a role in antiviral host defense by interacting with Bcl-2. The study also demonstrates that Beclin overexpression in virally infected neurons reduces Sindbis virus replication and prevents apoptosis, providing protection against fatal encephalitis. Beclin's Bcl-2-binding domain is essential for its antiviral and antiapoptotic effects. Beclin interacts with Bcl-2 and Bcl-xL, but not with Bax, indicating a selective interaction with death repressor members of the Bcl-2 family. Mutations in the Bcl-2 or Bcl-xL BH1 domain that block death repressor activity also block binding to Beclin, supporting the role of Beclin in antiviral defense. The study further shows that Beclin reduces Sindbis virus-induced cell death in mouse brains, with fewer apoptotic nuclei in mice infected with SIN/beclin compared to those infected with SIN/beclin ΔBcl-2BD or SIN/beclinstop. Beclin's protective effects are mediated through interactions with Bcl-2-like proteins, suggesting that Beclin functions as an antiviral host defense molecule in the central nervous system. The findings highlight the importance of Beclin in regulating Sindbis virus replication and preventing apoptosis in neural cells.This study identifies Beclin, a novel Bcl-2-interacting protein, as a potential antiviral host defense molecule that protects against fatal Sindbis virus encephalitis. Bcl-2, a well-known antiapoptotic protein, was previously shown to reduce Sindbis virus replication and prevent virus-induced apoptosis in mouse brains, thereby protecting against lethal encephalitis. Using a yeast two-hybrid screen, researchers identified Beclin, a 60-kDa coiled-coil protein that interacts with Bcl-2 in mammalian cells. Recombinant Sindbis viruses expressing full-length human Beclin (SIN/beclin) showed significantly higher survival rates in infected mice compared to viruses expressing Beclin lacking the Bcl-2-binding domain (SIN/beclin ΔBcl-2BD) or Beclin with a premature stop codon (SIN/beclinstop). Mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than those infected with the other viruses. These findings suggest that Beclin plays a role in antiviral host defense by interacting with Bcl-2. The study also demonstrates that Beclin overexpression in virally infected neurons reduces Sindbis virus replication and prevents apoptosis, providing protection against fatal encephalitis. Beclin's Bcl-2-binding domain is essential for its antiviral and antiapoptotic effects. Beclin interacts with Bcl-2 and Bcl-xL, but not with Bax, indicating a selective interaction with death repressor members of the Bcl-2 family. Mutations in the Bcl-2 or Bcl-xL BH1 domain that block death repressor activity also block binding to Beclin, supporting the role of Beclin in antiviral defense. The study further shows that Beclin reduces Sindbis virus-induced cell death in mouse brains, with fewer apoptotic nuclei in mice infected with SIN/beclin compared to those infected with SIN/beclin ΔBcl-2BD or SIN/beclinstop. Beclin's protective effects are mediated through interactions with Bcl-2-like proteins, suggesting that Beclin functions as an antiviral host defense molecule in the central nervous system. The findings highlight the importance of Beclin in regulating Sindbis virus replication and preventing apoptosis in neural cells.