This invention relates to herpes simplex virus (HSV) based vectors for delivering transgenes (e.g., a therapeutic gene) which are more resistant to neutralization, phagocytosis, and NK cells by immune systems, and methods for their preparation and treatment of disorders and diseases (such as those related to gene expression) with them. In one embodiment, the HSV vectors are prepared by treatment in immune sera that contain a high level of anti-HSV antibodies. The HSV vectors may include an extracellular CD47 domain inserted into the N-terminus of a glycoprotein in order to inhibit phagocyte activity, and the absence of gE for evading NK cells.