In various aspects, the invention relates to immune tolerant glycosidase therapy. The invention provides methods for treating or preventing infectious disease, including chronic viral infections, and highly contagious infectious agents that present an ongoing challenge for the immune system. The compositions and treatment regimens find use with other antiviral or antimicrobial therapies, as well as in conjunction with vaccination to boost effectiveness and/or extend the duration of protective effect. In certain embodiments, the regimen described herein reduces or eliminates the need for administration of other traditional antiviral or antimicrobial therapies. In various embodiments, the invention finds use in immunocompromised patients to boost immune function.