Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation

Abstract

Diagnosed in more than 90% of cervical cancers, the fourth deadliest cancer in women, human papillomavirus (HPV) is currently the most common pathogen responsible for female cancers. Moreover, HPV infection is associated with many other diseases, including cutaneous and anogenital warts, and genital and upper aerodigestive tract cancers. The incidence and prevalence of these pathologies vary considerably depending on factors including HPV genotype, regional conditions, the study population, and the anatomical site sampled. Recently, features of the cervicovaginal microbiota are found to be associated with the incidence of HPV-related diseases, presenting a novel approach to identify high-risk women through both blood and cervical samples. Overall, the HPV repartition data show that HPV infection and related diseases are more prevalent in developing countries. Moreover, the available (2-, 4-, and 9-valent) vaccines based on virus-like particles, despite their proven effectiveness and safety, present some limitations in terms of system development cost, transport cold chain, and oncogenic HPV variants. In addition, vaccination programs face some challenges, leading to a considerable burden of HPV infection and related diseases. Therefore, even though the new (9-valent) vaccine seems promising, next-generation vaccines as well as awareness programs associated with HPV vaccination and budget reinforcements for immunization are needed.

Keywords: HPV-related disease; cervicovaginal microbiome; epidemiology; human papillomavirus (HPV); intratypic molecular variant; molecular pathogenesis; natural history.

Figure 1

Structural representation of HPV and the L1 protein used as antigen in current vaccines. (A) The cryo-electron microscopy reconstitution of a whole HPV 18 viral particle, solved to a final resolution of 19 Å (82). (B) The viral genome representation of α-HPV (HPV18), constructed from the complete genome sequence of HPV18 (GenBank accession number NC_001357.1). All early and late ORFs, and the long control repeat (LCR) are shown in the respective proportions. (C–E) The crystal structure of HPV18 L1 pentamer, drawn from the PDB ID 2r5i, using PyMol (http://www.pymol.org/funding.html). (C) shows the top core structure of each L1 monomer in the capsomer in different colors revealing the surface loops serving as epitopes for neutralizing antibodies in VLP-based vaccines. (D,E) show the surface conformation in different views (top and side view), revealing each loop in different colors and some specific heparan-sulfate proteoglycan (HSPG) binding sites rich in lysine (K). Both variable and constant regions are clearly seen. The BC loop (49–66), DE loop (111–155), EF loop (169–190), FG loop (262–291), and HI loop (348–361) are clearly represented in (C–E).

Figure 2

Phylogenetic tree of HPVs. The 200 HPV L1 protein sequences used to build this tree were retrieved from NCBI using the BLASTn tool, from an HPV L1 protein sequence blast. This phylogeny reconstruction was based on the neighbor-joining method with 500 bootstrap replications using MEGA7 software. It shows that all the oncogenic HPV types are clustered together within the same alpha gender. The actually considered 17 HR-HPVs are presented as bold red dots.

Figure 3

HR-HPV infection cycle at the molecular level and progression to invasive cancer. Left: HPVs enter either through a microlesion on the upper layer or directly through the squamocolumnar junction, infecting basal keratinocyte cells. Sequential viral protein expression is shown (green arrow) according to the order of their synthesis throughout the productive infection. Once infected, cells can progress to a worse infection state characterized by viral DNA integration into genomic DNA and overexpression of E6 and E7 oncoproteins. The progression of infection to the development of invasive cancer, which takes place within a long period, depends on the intrinsic factors of the infected individual and/or extrinsic of the viral strain. Right: virus–receptor interactions from the attachment to the internalization on the epithelial cells during one infection cell cycle.

Figure 4

Cervicovaginal microbiome (CVM) features in HR-HPV infection natural history. This figure is an adaptation of the recently published study findings (123). The main characteristic of the CVM is its microbial diversity (Lactobacillus spp.—in purple, Vibrio and flagelled bacteria—in blue and green). Once an HR-HPV infection (red star) occurs in the 30–40% of exposed women (90%), few of them develop HPV-associated abnormalities such as low-grade cervical intraepithelial neoplasia (CIN1) or lesions, which can progress to high-grade lesion (CIN2-3) responsible in long term to invasive cervical cancers. In this figure, and as previously found, the abundance of Lactobacilus spp. is associated with a regression of viral persistence and a clearance of the infection. However, the progression of the infection to the precancerous lesions is associated with a subsequent increase in the microbiota variability, specifically Gardnerella vaginalis (in red) bacteria and some pathogenic fungi. The CVM may then serve to identify HPV-infected women with pre-cancer risk. The effect of Gardnerella on the CVM stability is involved in the HPV infection natural history.