Human papillomaviruses (HPVs) are small double-stranded DNA viruses that are highly species specific and possess a strict tropism for squamous epithelium. HPVs are designated as oncogenic based on the ability of a specific viral genotype to cause transformation in the host cell. Of the oncogenic types, HPV16 and HPV18 together cause over 60% of cervical cancers and HPV-16 is associated with 72% of HPV[+] oropharyngeal squamous cell carcinomas. Although prophylactic vaccines are very effective in preventing infection by HPV16 and HPV18, the uptake of the vaccines is poor in the US and many millions of people are already HPV infected. Further, HPV[+] head-and-neck cancer incidence is rising. The current heavy burden of HPV-related infections and diseases, as well as the morbidity and/or underachievement of current therapies, underscores the need for development of efficacious therapeutic strategies. Early proteins E5, E6, and E7 from oncogenic HPV types are known to regulate epidermal growth factor receptor (EGFR) gene transcription and activity in infected cells. Based on the fact that EGFR signaling activates AP1 transcription factors (TF) and previous studies indicating cellular AP1 TF regulate HPV gene expression, we hypothesize that HPV infection establishes an intracellular feed-forward loop with the EGFR signaling pathway that does not require high levels of EGFR expression. We posit that HPV-mediated gene expression results in increased EGFR signal transduction leading to enhanced viral transcription through modulation of cell survival and proliferation signals. Preliminary data show initiating a break in EGFR-pathway signaling has anti-viral effects to cause down regulation of HPV oncoprotein expression in infected cells, leading to recovered p53 and pRb activity. Specific Aims are designed to determine if this anti-viral activity occurs in HPV+ HNSCC cell lines, and whether cells are rendered more susceptible to chemotherapy and radiation and/or have decreased tumorigenicity. We expect to determine how EGFR signaling cascades regulate HPV gene expression in infected cells that maintain episomal or integrated viral genomes. Our scientific expertise in HPV biology and tumorigenesis makes us uniquely suited to carry out this work. Understanding the anti-viral mechanism of EGFR pathway inhibitors stands to lead to more efficacious and less toxic therapeutic strategies in clinical trials. Additionally, we will learn critical aspects of the interplay between host and virus that may underlie progression to cancer and/or prognosis of HPV[+] lesions.