Project Summary/Abstract: Research in the field of microbiome has largely focused on the beneficial effects of commensal bacteria in regulating tissue homeostasis and the immune responses. However, a commensal role for virome in supporting human health has not been explored. We propose to investigate the commensal virome and its beneficial impact on tissue homeostasis and cancer protection in barrier epithelia. Informed by our recent discovery of the beneficial role of low-risk commensal papillomaviruses and the immunity against them in protecting the skin against carcinogen-driven cancer, we propose a completely novel approach to prevent nonviral cancers by using the patients’ own virome and the immune system to precisely target early malignant clones within the barrier epithelia. In particular, the widespread presence of commensal human papillomaviruses (HPVs) in barrier epithelia and the ability of a competent immune system in adults to control these viruses will provide a unique opportunity to determine the interplay of commensal viruses, epithelial tumors and the immune system. To accomplish this, we will use novel mouse models of papillomavirus colonization to (1) determine the impact of commensal HPVs on maintaining the homeostasis of epithelium exposed to environmental carcinogens, (2) identify the innate immune factors that are required for the activation of antiviral T cells targeting malignant cells while spare the virus-positive normal tissue, and (3) determine the role of papillomaviruses that colonize the oral mucosa on the carcinogen-induced head and neck cancer. The outcomes of the proposed research will establish a fundamental role for commensal virome in combating the early stages of cancer development and provide the means to prevent and treat nonviral epithelial cancers using patients’ own virome and the immune cells.