Mucosal and Cutaneous Human Papillomavirus Infections and Cancer Biology

Abstract

Papillomaviridae is a family of small non-enveloped icosahedral viruses with double-stranded circular DNA. More than 200 different human papillomaviruses (HPVs) have been listed so far. Based on epidemiological data, a subgroup of alphapapillomaviruses (alpha HPVs) was referred to as high-risk (HR) HPV types. HR HPVs are the etiological agents of anogenital cancer and a subset of head and neck cancers. The cutaneous HPV types, mainly from beta and gamma genera, are widely present on the surface of the skin in the general population. However, there is growing evidence of an etiological role of betapapillomaviruses (beta HPVs) in non-melanoma skin cancer (NMSC), together with ultraviolet (UV) radiation. Studies performed on mucosal HR HPV types, such as 16 and 18, showed that both oncoproteins E6 and E7 play a key role in cervical cancer by altering pathways involved in the host immune response to establish a persistent infection and by promoting cellular transformation. Continuous expression of E6 and E7 of mucosal HR HPV types is essential to initiate and to maintain the cellular transformation process, whereas expression of E6 and E7 of cutaneous HPV types is not required for the maintenance of the skin cancer phenotype. Beta HPV types appear to play a role in the initiation of skin carcinogenesis, by exacerbating the accumulation of UV radiation-induced DNA breaks and somatic mutations (the hit-and-run mechanism), and they would therefore act as facilitators rather than direct actors in NMSC. In this review, the natural history of HPV infection and the transforming properties of various HPV genera will be described, with a particular focus on describing the state of knowledge about the role of cutaneous HPV types in NMSC.

Keywords: Papillomavirus; anogenital cancer; infection and cancer; skin cancer; transformation.

Figure 1

Genome organization of alpha and beta HPV types. The circular dsDNA genome of high-risk alpha and beta HPV types is represented by a black circle. The positions of the early and late genes are represented by blue and orange, respectively. Both represented PV genera have the potential to express an E8^∧E2C transcript that encodes for a protein that includes an E8 domain fused to the hinge and DNA-binding domains of E2. LCR, long control region.

Figure 2

Entry of HPV. The virus binds to the heparan sulfate chains of proteoglycans (HSPGs) located on the cell membrane or on the extracellular matrix through the major capsid protein L1, which leads to the conformational change of the capsid and the subsequent L2 externalization on the surface of the viral particle. Next, the N-terminus of the minor capsid protein L2 is cleaved at a conserved furin cleavage consensus site, which facilitates the binding of HPV to an unidentified secondary receptor, allowing subsequent internalization that is actin-dependent. The L2–viral DNA complex and a portion of L1 are delivered to the trans-Golgi network, through retromer- and retriever-mediated vesicular trafficking. Inside the late endosomes, the capsid of the viral particle is disassembled in a low-pH environment, leading to the dissociation of the major capsid protein L1 from the minor capsid L2, mediated by host-cell cyclophilins. The L2–viral DNA complex is then delivered into the nucleus to the nuclear domain (ND10), during cell mitosis.

Figure 3

Life cycle of HPV. The first step of the replication cycle of HPV, called “establishment replication,” consists of maintaining a constant number of episomal copies. Viral DNA replication relies on the host DNA replication machinery and is supported by the early viral proteins E1 and E2. After this initial step, the maintenance phase is initiated. This phase consists of creating the conditions to maintain a constant number of viral genomes in the nuclei of undifferentiated basal cells as an extrachromosomal genome to create a persistent infection. In addition to E1 and E2, the oncoproteins E6 and/or E7 are required for stable episomal maintenance of HPV. Upon cell differentiation in stratified epithelium, vegetative or productive viral replication is initiated, with the subsequent production of progeny virions. Here, the oncoproteins E6 and E7 expressed at relatively low levels in differentiated cells play a key role by inactivating tumor suppressor proteins. The activation in differentiated epithelial cells of the late promoter, located in the E7 region, leads to the production of the high levels of E1 and E2 viral proteins required to ensure viral DNA replication. E4 and E5 contribute to efficient productive replication. The capsid proteins L1 and L2 are expressed from the late promoter, and are involved in the encapsidation of newly replicated genomes, resulting in virion release in the superficial layers during desquamation. E4 also plays a role at this step of the viral life cycle, by interacting with the keratin network. The right side of the schematic representation illustrates that a minority of HPV infections become persistent, thus increasing the risk of keratinocyte transformation, through integration of viral DNA into the human genome, which leads to the loss of E2 repression function and subsequent E6 and E7 upregulation.