Papillomaviruses: Viral evolution, cancer and evolutionary medicine

Abstract

Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mammals. PVs cause infections without triggering a strong immune response, and natural infection provides only limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some cases, infections by certain PVs take diverse clinical presentations from highly productive self-limited warts to invasive cancers. We propose PVs as an excellent model system to study the evolutionary interactions between the immune system and pathogens causing chronic infections: genotypically, PVs are very diverse, with hundreds of different genotypes infecting skin and mucosa; phenotypically, they display extremely broad gradients and trade-offs between key phenotypic traits, namely productivity, immunogenicity, prevalence, oncogenicity and clinical presentation. Public health interventions have been launched to decrease the burden of PV-associated cancers, including massive vaccination against the most oncogenic human PVs, as well as systematic screening for PV chronic anogenital infections. Anti-PVs vaccines elicit protection against infection, induce cross-protection against closely related viruses and result in herd immunity. However, our knowledge on the ecological and intrapatient dynamics of PV infections remains fragmentary. We still need to understand how the novel anthropogenic selection pressures posed by vaccination and screening will affect viral circulation and epidemiology. We present here an overview of PV evolution and the connection between PV genotypes and the phenotypic, clinical manifestations of the diseases they cause. This differential link between viral evolution and the gradient cancer-warts-asymptomatic infections makes PVs a privileged playground for evolutionary medicine research.

Keywords: HPV; infection and cancer; molecular epidemiology; screening; vaccination; viral oncology; virus ecology cancer; virus evolution.

Figure 1.

Genome organization and life cycle of PVs. (A) Schematic representation of PV dsDNA genome, exemplified on HPV16, showing the location of the early (E) and late genes (L) and of the URR. (B) Summary of PV genes functions. Genes involved in similar functions are indicated with similar colours: green, genes implicated in oncogenesis; orange, viral replication genes and blue, viral capsid genes. (C) Schematic view of the PV16 life cycle. The squamous epithelium is represented on the left and the genes expressed in each stage of the keratinocyte differentiation program are noted at the right. PVs infect keratinocytes in the basal layer of the epithelium that become exposed through microwounds. The viral genomes are established in the nucleus as low-copy episomes and early viral genes are expressed. The viral genomes are replicated in synchrony with cellular DNA replication. After cell division, one daughter cell migrates away from the basal layer and undergoes differentiation. Differentiation of HPV-positive cells induces the productive phase of the viral life cycle, which requires cellular DNA synthesis machinery. The expression of E6 and E7 deregulates cell cycle control, pushing differentiating cells into S phase, allowing viral genome amplification in cells that normally would have exited the cell cycle. The late-phase L1 and L2 proteins encapsidate newly synthesized viral genomes and virions are shed from the uppermost layers of the epithelium

Figure 2.

PV phylogeny reconstruction. Best-known maximum likelihood nucleotide phylogenetic tree of the concatenated E1E2L1L2 gene sequences of full-length 263 PV genomes. Phylogenetic reconstructions yield four well-supported PV supertaxa. Colour code highlights the four crown groups: red, Alpha-Omikron-PVs; green, Beta-Xi-PVs; ochre, Lambda-Mu-PVs; blue, Delta-Zeta-PVs and white, PVs without well-supported phylogenetic relationships. Branches in black correspond to HPVs and branches in grey to non-HPVs. Outer labels indicate the most common tropism for the groups encompassing HPVs. Carcinogenicity of HPVs is indicated: a black dot indicates International Agency for Research on Cancer (IARC) group 1; a white dot indicates IARC groups 2A or 2B. Animal PVs with carcinogenic potential are marked with a black triangle. Asterisks on branches correspond to ML bootstrap support values. Two asterisks indicate maximal support values; one indicates support values between 90 and 50; and values under 50 are not shown

Figure 3.

Classification of carcinogenicity used by the International Agency for Research on Cancer (IARC). IARC’s programme relies on international working groups of scientists expert in the particular area under investigation. The working groups analyze the information from case reports and epidemiological studies on humans, animal studies and other relevant biological data to evaluate the carcinogenicity of different agents to humans. Agents are classified into one of the four carcinogenicity groups. (Data extracted from IARC Monographs vol. 100B and 104.)

Figure 4.

Evolution of the number of PV sequences available in the GenBank. Data have been extracted at the level of type for the genera encompassing PVs infecting humans: Alpha-, Beta-, Gamma-, Mu- and NuPVs. The evolution of the number of different full-length genome HPV16 variants is also shown. The trends in the number of sequences available indicate that although the members of AlphaPVs, the best-studied PVs, have reached a plateau, the number of Beta- and GammaPVs is still increasing. Only three members within Mu- and NuPVs have been described. Although largely undersampled and constantly growing, the number of animal PVs represents one-third of the global known PV diversity

Figure 5.

Global scenario of PV evolution. (A) Ancestral amniotes were already infected by ancestral PVs. The four PV crown groups (labelled in red, green, blue and orange) appeared during the evolution of skin glands and hairs (250–150 Mya). Subsequent mammalian radiation triggered further a second wave of PV diversification (110-60 Mya). (B) Zoom into the evolutionary scenario for lineages in the Alpha-Omicron-PVs crown group, with individual, rare events largely influencing the evolutionary history. A recombination event yielded a novel viral lineage with the early genes from an Alpha-Omicron-PV infecting cetaceans and the late genes from a Beta-Xi-PV infecting artiodactyls. Separately, in a PV lineage infecting the ancestor of Old World monkeys and apes, an integration event between the E2 and the L2 genes introduced a DNA segment encoding for the ancestral E5 ORFs. This integration triggered an adaptive radiation that generated three viral lineages with different tropism and different clinical manifestations. In one of these lineages, the E6 proteins acquired the ability to degrade p53. Some viruses in this lineage are responsible for anogenital and oropharyngeal cancers in humans

Figure 6.

Fraction of anogenital cancers caused by HPVs infections preventable through vaccination. Data should be read as follows, with vaginal cancer as an example: every year, 9,000 new vaginal cancer cases are diagnosed worldwide, and 74% of them are associated to infection by HPVs. This is known as PAF, Population Attributable Fraction. From these, 77.1% are associated to HPV16 or HPV18, and could be prevented using the bivalent or the quadrivalent vaccine; 0.9% are associated to HPV6 or HPV11, and could be prevented by the quadrivalent vaccine; 13.7% of the rest of HPV-related cases are associated to HPV31, HPV33, HPV45, HPV52 and/or HPV58, and could be prevented using the nonavalent vaccine; the remaining 8.3% of the vaginal cancer cases are not targetted by any current vaccine. Data extracted from the Catalan Institute of Oncology HPV Information Center, last queried on June 2014 (http://www.hpvcentre.net/)