In a virus-associated tumor environment, the recruitment of these regulatory cells is often increased, which can enhance viral immune evasion. (23). Overall, -HPV DNA is detected in 30C50% of NMSCs from immunocompetent patients (24), and 90% of NMSCs from immunosuppressed patients (25, 26). Although -HPVs are present at very low viral loads in diseased skin (27), and are usually considered as a part of microbiota in healthy human Lenalidomide-C5-NH2 skin (28), the deleterious effects of -HPVs on the host DNA repair pathway and cell cycle regulation responding to UV exposure has been recently studied and reviewed (18). LPA receptor 1 antibody It remains to be discovered whether there is a etiological role of -HPVs in NMSC initiation. Basics of HPV Biology HPV Genome and Life Cycle HPVs are small, double-stranded DNA viruses. Their genome contains ~8,000 base pairs which form eight or nine open reading frames (29) that are designated as early (E) or late (L). The early genes, which encode the viral proteins E1CE7, have multiple roles in viral genome replication, cell cycle entry, immune modulation, and virus release. Their expression occurs throughout the viral life cycle but reduces during later stages of infection. In contrast, the late genes, which encode the viral capsid proteins L1 and L2, are highly expressed during later stages of infection (30). Lenalidomide-C5-NH2 HPVs exclusively infect human epithelial cells, and more specifically, basal keratinocytes. It has been suggested that infection requires epithelial wounding to allow viral access to the basal lamina, where basal keratinocytes are located (30, 31). Virus entry is initiated by the L1 and L2 proteins (32C35). After entering into basal keratinocytes, the viral genome is transported into the nucleus and is maintained as episomal DNA (36). The life cycle of HPV can be divided into a non-productive Lenalidomide-C5-NH2 and a productive stage. In the non-productive stage, viral episomal DNA is amplified to 50C100 copies per cell in the nucleus of proliferative basal cells (37). Viral gene expression is minimal during this stage. The infected basal cells then leave the cell cycle and enter into the differentiation process, during which HPV begins its Lenalidomide-C5-NH2 productive stage. In this stage, HPV significantly increases its DNA amplification and gene expression activity (38). In order to utilize the host’s DNA replication machinery, which is suppressed in differentiating cells, HPV expresses the E1 helicase protein to facilitate access to single stranded viral DNA for replication, and the E6 and E7 oncoproteins to delay cell differentiation. E6 protein forms a complex with tumor suppressor protein p53 and recruits ubiquitination enzymes to degrade p53, preventing premature cell death. E7 protein on the other hand, disrupts the binding between retinoblastoma (Rb) protein and the E2F transcription factor, allowing the release of E2F to activate transcription of S-phase promoting genes in the host cells. The combination of E6 and E7 protein expression overrides cell cycle checkpoints and therefore allows HPV to replicate (39, 40). In the upper layers of the epithelium, HPV copy number Lenalidomide-C5-NH2 is markedly increased up to thousands per cell. Viral capsid proteins are synthesized and assembled in the terminally differentiated cells. The assembled capsid proteins form a coat that encapsulates viral genomes, and HPV is then shed from differentiated infected epithelial cells (30, 41). HPV Pathogenesis HPV-associated carcinogenesis has been extensively studied in the human genital tract, where around 30 strains are known to cause infection. These HPVs can be divided into high-risk genotypes (e.g., HPV16 and 18) that are associated with genital cancers, and low-risk genotypes (e.g., HPV6 and 11) that are typically found within genital warts or normal genital epithelium (30). HPV infections of the genital tract are sexually transmitted, and most individuals that partake in sexual activity will become infected by at least one genital HPV type in their lifetime. High risk HPV infection in the female genital tract initially causes low-grade squamous intraepithelial lesions (LSIL), also known as cervical intraepithelial neoplasia grade 1 (CIN 1). These lesions, within which viral replication occurs, show only mild dysplastic changes. They are usually cleared by the immune system within 1 year (42)..