The genetic features of HPV-positive OSCCs. A schematic depicts host-virus genetic interactions and features of HPV-positive OSCCs. HPV infection, represented by the viral capsid (center), is a necessary initiating event but insufficient for the development of cancer. Secondary genetic alterations accumulate as a consequence of host genomic instability induced by HPV oncoproteins, APOBEC induced host genome editing, and other forms of DNA mutagenesis. HPV E6*1, E6, E7, and E5 oncoproteins and these recurrent somatic variants in host genes and pathways cooperatively disrupt host genomic stability, apoptosis, cellular proliferation, epithelial differentiation, the anti-viral immune response, and transcriptional regulation. These viral-host interactions coordinately shape the genomes of HPV-positive OSCCs to promote HPV infection persistence, carcinogenesis, and tumor immune evasion.