Multiple Human Papillomavirus Infections in the Development of CIN

Plain-language summary

Multiple infections of high-risk genotypes of Human Papillomavirus (HR-HPV) in patients with abnormal cervical cytological or histological findings are detectable in a percentage ranging from 20% to 50% of cases. Some studies have detected a certain tendency to specific clustering in multiple infections, both inter-species and inter-genotypic, such as HPV 31-35-56, HPV 16-51-52, HPV 16-18, HPV 51-52. Furthermore, a greater tendency of the HPV16 genotype to cluster with genotypes of different species is reported in the literature. However, other studies claim a random character of such genotypic associations in multiple infections. This heterogeneity of results of the studies present in the literature underlies multiple factors, both epidemiological and methodological, implicated in the high variability of prevalence and diagnostic findings of multiple infections. In particular, with regard to epidemiological characteristics, factors influencing the distribution of multiple infections appear to be the origin and type of population, economic-social status, young age, HIV seropositivity and recent sexual activity. A further hypothesized element is represented by a possible individual susceptibility dictated by the immune profile of the host towards specific genotypes, potentially facilitating the occurrence of co-infections by these, possibly resulting in a synergistic effect on the oncogenic potential. From a clinical point of view, to date multiple cross-sectional studies suggest an association between multiple infections of HR-HPVs and an increased risk of high-grade cervical dysplasia. In particular, a proportional relationship is observed between the number of genotypes present and the severity of the lesion. Furthermore, it has been reported that the correlation between multiple HR-HPV infections and severe cervical dysplasia CIN2+ is significant both in the presence and absence of the known oncogenic genotype HPV16, assuming a possible synergistic interaction between specific high-risk genotypes. However, other studies seem to refute the clinical relevance of multiple infections in the risk of neoplastic progression of cervical lesions, mostly claiming the precept of "one virus, one lesion", such that each dysplastic lesion is associated with the action of a distinct HR-HPV genotype. In this assumption, therefore, it is argued that moderate-severe cervical dysplasias are due to the action of a single oncogenic genotype, predominantly HPV16, while the presence of other HR-HPVs is attributable to transient infections, mostly represented by mild dysplasias (CIN1). As far as biological knowledge is concerned, in vitro studies currently demonstrate how it is possible for a single cell to be co-infected by at least two HR-HPV genotypes and how this can result in peculiar inter-genotypic molecular interactions that influence the replication cycle and the respective capacity for cellular persistence and transformation of the individual genotypes involved. The inter-genotypic competition mechanisms detected, therefore, occur mostly during the initial phases of acute infection by the HR-HPVs involved. However, it has been demonstrated that when a persistent infection of a genotype has already been established, this is no longer able to negatively interact with a subsequent incident infection by a different HR-HPV genotype. This finding in the biological field is consistent with the clinical correlate according to which the association between multiple HR-HPV infections and the risk of high-grade cervical dysplasia is greater when these are established on a pre-existing persistent infection. Therefore, it is conceivable that there is a higher rate of genotype-specific association in multiple HR-HPV infections found in cervical dysplastic lesions, defined by the peculiar capacities of the individual genotypes to give rise to persistent cellular infections. Despite the proven efficacy of vaccination programs in preventing cervical dysplastic lesions and infection by the main viral genotypes with high oncogenic risk, numerous studies demonstrate the clinical efficacy of HPV vaccination also in reducing the rate of disease recurrence in patients undergoing excisional treatment. A first explanatory hypothesis of this phenomenon is represented by the protection that the vaccination procedure would provide to those patients not previously infected by the target HR-HPV genotypes, potentially causative of de novo infections with high oncogenic risk. A further hypothesis under study is represented by the fact that the administration of the HPV vaccine following excisional treatment would prevent the reduction of the immune response against HPV.

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