Oral manifestations of human papillomavirus infections

Abstract

Papillomaviruses are one of the oldest viruses known, dating back 330 million years. During this long evolution, human papillomaviruses (HPV) have developed into hijackers of human cellular and immune systems in which they replicate and remain silent. Systematic studies on oral HPV infections and their outcomes are still scarce. Oral HPV infections have been linked to sexual behaviour, but recent evidence supports their horizontal, mouth-to-mouth, transmission. Most HPV infections in infants are acquired vertically from the mother during the intrauterine period, during delivery, or later via saliva. The best-known benign clinical manifestations of HPV infection are oral papilloma/condyloma and focal epithelial hyperplasia. Evidence is emerging which suggests that some oral HPV infections might persist. Persistent HPV infection is mandatory for HPV-associated malignant transformation. However, progression of HPV-induced lesions to malignancy requires additional cofactors. In the early 1980s, we provided the first evidence that a subset of oral cancers and other head and neck cancers might be causally linked to HPV infection. This review summarizes current knowledge on the virus itself, its transmission modes, as well as the full spectrum of oral HPV infections - from asymptomatic infections to benign, potentially malignant oral lesions, and squamous cell carcinoma.

Keywords: human papillomaviruses; oral infection; prevention; saliva; transmission.

Figure 1

Human papillomavirus (HPV) genotypes among species of the genus Alphapapillomavirus. The species containing high‐risk and low‐risk HPV genotypes are marked with pink and green colors, respectively. Reprinted from Rautava J and Syrjänen S. Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis. Head Neck Pathol. 2012; 6(Suppl 1): 3–1. With permission from Springer Nature via Copyright Clearance Center's RightsLink service.

Figure 2

Organization of the human papillomavirus (HPV) genome. Early genes (E1, E2, E4, E5, E6, and E7) code for non‐structural proteins, while late genes (L1 and L2) code for structural proteins. The long control region (LCR) contains a DNA replication origin and several binding sites for viral and host proteins to regulate viral DNA replication. The two major promoters P97 and P670 are marked. HPV can integrate into the host cell chromosome in a random pattern. During this integration, the double‐stranded circular DNA opens, which will disturb the function of the E2 gene, as given in the lower graph. Reprinted from Rautava J and Syrjänen S. Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis. Head Neck Pathol. 2012; 6(Suppl 1): 3–1. With permission from Springer Nature via Copyright Clearance Center's RightsLink service.

Figure 3

Human papillomavirus (HPV) infects the basal cells of the stratified squamous epithelia which become exposed after wounding or micro trauma. Virus particles are produced only in the surface of the epithelium, from where they are shed into the surroundings to infect new target cells. In the nuclei of basal cells, the viral genome remains as a low‐copy plasmid. Expression of viral proteins is regulated by differentiation of the infected cells during their movement toward the epithelial surface. At an early stage of the infection, viral DNA is replicated, along with cellular DNA, during cell division at S‐phase. At some point, a switch from stable replication (genome maintenance) to vegetative viral DNA replication will occur to allow the production of genomes for packaging into virions encapsulated by L1 and L2. Thousands of virus particles are produced per cell. After viral integration of high‐risk HPVs, the expression of E6 and E7 genes are permanently upregulated. HPV E6 binds and degrades p53, which leads to inhibition of apoptosis. HPV E7 protein binds and degrades the retinoblastoma tumor suppressor protein, pRB, disrupting its interaction with the transcription factor E2F. The release and activation of E2F results in expression of S‐phase genes and cell‐cycle progression. Upregulation of p16 is induced by HPV‐mediated disruption of E7, which leads to cellular accumulation of p16.

Figure 4

The prevalence of asymptomatic human papillomavirus (HPV) in oral brush samples taken from healthy young couples at entry to the Finnish Family HPV Study. In total, 17% of the oral samples in women tested HPV DNA positive, while 18.7% of the oral samples taken from their male spouses were HPV DNA positive. The HPV genotype distribution among the HPV‐positive samples is presented in the pie charts. The outcome of oral HPV infection in women and their male spouses during the 6‐yr follow‐up is given in references 39, 40, 51, 54. neg, negative.

Figure 5

Schematic presentation of the stepwise progression of a human papillomavirus (HPV)‐infected cell toward carcinogenesis. Reprinted from Rautava J and Syrjänen S. Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis. Head Neck Pathol. 2012; 6(Suppl 1): 3–1. With permission from Springer Nature via Copyright Clearance Center's RightsLink^® service.