Following infection with herpes simplex virus type 1 (HSV-1) the host recognizes viral nucleic acids which then initiates a signaling cascade leading to the activation of the immune system and creating a cellular environment unfavorable for viral replication. A well-characterized anti-viral response to HSV-1 infection is mediated by the double-stranded RNA dependent protein kinase (PKR). Cellular stressors activate PKR which in turn phosphorylates the translation initiation factor eIF2α. Phosphorylated eIF2α sequesters the eIF2 ternary complex resulting in inhibition of translation. In order for the virus to replicate and cause disease in the host it encodes a number of proteins which counteract the innate immune response. One such protein is ICP34.5 which has been shown to have a domain in its C-terminal region that contains homology to mammalian proteins which bind to protein phosphatase 1 (PP1). This domain mediates binding to PP1α which redirects the phosphatase to dephosphorylate eIF2α allowing translation to ensue despite the presence of activated PKR. A second function of ICP34.5 is binding Beclin 1 and regulating the induction of autophagy. This interaction occurs at the N-terminus of ICP34.5 suggesting that these are separable functions of the protein. An HSV-1 mutant which lacks ICP34.5 has a severe replication defect both in vitro and in vivo. While regulation of autophagy does not impact HSV-1 replication in primary cultured cells, PP1α binding and antagonism of translational arrest is required for efficient in vitro growth. However, an ICP34.5 mutant which is unable to bind Beclin 1 displays reduced neurovirulence and replication, and causes less disease in mice following both intracranial and corneal infection. Neurovirulence of this mutant is restored in mice which lack PKR or T and B lymphocytes suggesting that both the innate and adaptive immune systems are interconnected with the autophagy pathway. Taken together, these data demonstrate that autophagy is a critical anti-viral mechanism of the host, and ICP34.5 in part through Beclin 1 binding can overcome this host defense and cause lethal disease.