The HPV genome is a 7.9 kb double-stranded circular genome. The genome is controlled by a single keratin-dependent promoter element; the long control region (LCR; in blue). At the 3′ end of the LCR is the origin of replication (nucleotide position 1). E6, E7 (red), and E5 are viral oncogenes; E1 and E2 early genes encode replication proteins. The E4 ORF is actually expressed early and late in the viral life cycle. The late genes, L1 and L2, are the major and minor capsid genes, respectively. The viral protein functions are detailed in Table I.

The HPV life cycle. Virions enter the stratified epithelium through a site of wounding, where they gain access to the mitotically active basal-layer keratinocytes. During the maintenance phase, expression of E6, E7, and E5 induces cell proliferation, and the viral genome is replicated extrachromosomally at low-copy number (5-50 copies per cell). As the cells differentiate, the expression level of E1, E2, and E4 increases in the spinous layer. A transition from theta to rolling-circle replication results in an increase in copy number up to 100-1000 copies per cell. Postamplification, high levels of L1 and L2 capsid genes are expressed and capsid assembly occurs in the granular and squamous layers of the stratified epithelium. Progeny virus is released by desquamation.

Progression from a benign cervical lesion to invasive cervical cancer. In the diagram, HPV-positive cells are depicted by yellow nuclei. Infection by oncogenic HPV types, especially HPV16, can cause formation of a benign wart, low or high-grade dysplasia- r. CIN 1 and CIN 2 designations are reversible forms of precancerous lesions and CIN 3 is irreversible. Carcinoma in situ occurs many years after an infection. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.

Diagram of the role of E6 and E7 in disregulation of the cell cycle. Expression of E6 leads to recruitment of E6AP (a ubiquitin ligase). This complex causes degradation of p53, which then inhibits the p21-dependent block of the G₁ to S transition. Similarly, E7 binding to Rb displaces E2F, resulting in Rb’s degradation. E2F can then activate expression of cyclin E and other S-phase related gene products.

The rate of advancement of HPV lesions, from benign hyperplasia to carcinoma in situ, is affected by additional factors, which includes immunocompetence. HIV status, alcohol, drugs, smoking, oral contraceptives, and hormone levels influence HPV infection and progression of HPV-induced cancers. High-risk HPVs, HPV coinfection, variants, genome integration, and infection of other STDs affect the propensity for HPV-induced cancer to occur and progress.