Human papillomaviruses (HPV) are naked particles composed of 72 subunits, each formed by 2 structural proteins designated L1 and L2 (L = late). HPV does not grow outside of squamous epithelium cells, in which it infects the suprabasal prickle cell layer. The viral double-stranded DNA (vDNA) has about 8 kilobase pairs (kbp) and also encodes several non-structural polypeptides, designated E1–E7 (E = early). At least 3 early oncoproteins (E5, E6, and E7) induce host cell proliferation, driving them into permanent division. During long-term latency, the circularized HPV DNA may get integrated into the host cell DNA molecule. The circular HPV DNA is then interrupted, usually within the E2 open reading frame (ORF), which then cannot exert its regulatory (feedback) effect on the early gene expression. The increased expression of E6/E7 proteins seriously affects the regulation of host cell division mainly via dysregulation of the functions of p53 and Rp proteins. HPV infects the female genital tract representing the main cause of cervical dysplasia and subsequent squamous cell carcinoma (SCa). The HPV isolates exist mainly in the form of amplified DNAs; based on the similarity and/or variations (dissimilarity) of their L1 capsid polypeptide sequence, 96 human genotypes were included into five genera of the Papillomaviridae family. The clinically most important genotypes that cause lesions at mucosal membranes and/or on the skin, belong mainly to the Alphapapillomavirus genus. The genotypes, associated with severe dysplastic changes and/or cervical cancer, were designated as high risk (HR-HPV). The prevalence of the integrated HPV DNA sequence over the episomal molecules appears in a proportion smears-graded LSIL (low-grade squamous intraepithelial lesion). Later on, carrier cells revealing the integrated HPV genome expression the oncoproteins (E6/E7) clearly prevail especially in HSIL (high-grade squamous intraepithelial lesion) smears and in the cervical cancer itself. What is crucial for the modern diagnostic of cervical dysplasia, is the p16/INK4A (inhibitor kinase) polypeptide, which itself represents a form of cell defense against the viral oncogenic proteins. The p16 antigen shows a continuous parabasal staining in the CIN I lesion. If dysplastic cells occupy at least one half (or two thirds) of squamous epithelium, the designation CIN II/HSIL is correct, and at the stage of CIN III/HSIL, dysplastic cells replace the entire squamous epithelium. Another frequently used immunohistochemical marker of intraepithelial cervical dysplasia so far is the Ki-67 antigen, which occurs in the nuclei of proliferating and/or repeatedly dividing (immortalized) cells. Women revealing p16-positive ASCUS (atypical smear cells of unknown significance) as well as those showing LSIL (low-grade cytological changes) should be examined for the presence of the HPV DNA. The detection of HPV DNA alone, that is, in the absence of cytological screening, has a relatively lower prediction value, though the HR HPV positive DNA test in the absence of morphological alterations may in part predict the possible progression into malignancy. Nevertheless, only the combined cytological as well as molecular follow-up (cervical smear examined for cytology as well as for HPV DNA) is regarded for the most reliable diagnostic approach.
Part of the book: Human Papillomavirus
This chapter is devoted to the topics of not yet marketed HSV vaccine, which is still in the focus of interest, especially from the point of immunotherapeutic use. To understand the principles of vaccination strategies (prophylactic and/or immunotherapeutic), the pathogenesis of herpes simplex virus 1 (HSV-1) and/or HSV-2 infections in animal models is briefly outlined. Even when both herpesviruses may spread via bloodstream, which is especially true in the immunocompromised host, the main route of their transmission is along peripheral nerves. Both viruses establish latency in ganglion cells, and after reactivation, they spread along axons back to the site of primary infection. Since neither the establishment of latency nor its reactivation can be fully controlled by virus-neutralizing antibodies, the outcome of immune response greatly depends on the activity of cytotoxic CD8+ T lymphocytes. The majority of important antigenic epitopes is located in envelope glycoproteins (such as gB, gD, gE, gC and gG) that are related to virus adsorption and penetration into susceptible cells. The HSV-1 and/or HSV-2 experimental vaccines designed so far were either purified virion products derived from infected cells (subunit vaccines), purified recombinant immunogenic herpes simplex virus HSV-coded proteins (especially gD), and/or attenuated live viruses lacking some of virulence tools (such as gH and/or gE). We bring a comprehensive overview of the efficacy of experimental HSV-1/HSV-2 vaccines and discuss our own data. In conclusion, we believe in the continued demand of HSV-1 and HSV-2 vaccines, at least for their immunotherapeutic use, suggesting unified evaluation criteria for clinical trials to reach consent at their interpretation.
Part of the book: Herpesviridae