Linear viral load increase of a single HPV‐type in women with multiple HPV infections predicts progression to cervical cancer

Abstract

Persistent high-risk human papillomavirus (HPV) infection is strongly associated with development of high-grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type-specific viral-load measurements predict the natural history of the infection. In infections with multiple HPV-types, the individual type-specific viral-load profile could distinguish progressing HPV-infections from regressing infections. A case-cohort natural history study was established using samples from untreated women with multiple HPV-infections who developed CIN3+ (n = 57) or cleared infections (n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real-time qPCR-assay (18 HPV-types). Using serial type-specific viral-load measurements (≥3) we calculated HPV-specific slopes and coefficient of determination (R(2) ) by linear regression. For each woman slopes and R(2) were used to calculate which HPV-induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV-types, each single HPV-type generated similar increasing (0.27copies/cell/day) and decreasing (-0.27copies/cell/day) viral-load slopes. In CIN3+, at least one of the HPV-types had a clonal progressive course (R(2) ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases (n = 6), immunostaining detecting type-specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion-producing infections the RNA-staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly-formed virions. RNA-hybridization patterns matched the calculated ongoing processes measured by R(2) and slope in serial type-specific viral-load measurements preceding the biopsy. In women with multiple HPV-types, serial type-specific viral-load measurements predict the natural history of the different HPV-types and elucidates HPV-genotype attribution.

Deep sequencing of HPV E6/E7 genes reveals loss of genotypic diversity and gain of clonal dominance in high-grade intraepithelial lesions of the cervix

“…Together, these metagenomic characteristics are consistent with the ecological principles of competitive exclusion and carcinogenesis hallmarked by clonal expansion and evolution of transformed cells as illustrated in Fig. 6 [34–40]. The distinguishing features of altered diversity and dominance between HPV communities may serve well as a biomarker for disease severity.…”

“…6Schematic diagram of evolving virus-host interactions on the cervix. After infection (left), virus-virus (middle) and virus-host (right) interactions based on the principles of competitive exclusion and clonal evolution of cancer are illustrated [34–40]. Gause’s law of competitive exclusion states that between two competing species, the species with the slightest advantage will ultimately dominate [34, 35].…”

Human papillomavirus type 16 and 18 viral loads as predictors associated with abnormal cervical cytology among women in Saudi Arabia

“…In an interesting study, HPV viral load was assessed after surgical removal of the cervical tumor, and the researchers found that viral load was associated with disease progression but not with cytology grade or age [20]. However, another study found that viral load was a significant predictor associated with the progression of cervical cancer in patients with multiple infection [11]. In our population, only 8 patients had multiple HPV infection.…”

“…In diseases related to viral infections, viral load has been shown to be a promising marker for clinical progression [8,9,10]. Although HPV viral load has been showing great potential in predicting cytology abnormalities [11], many studies have reported conflicting results, which may be attributable to their small sample sizes or their use of different types of detection assays [12].…”

A Genetically Modified attenuated Listeria Vaccine Expressing HPV16 E7 Kill Tumor Cells in Direct and Antigen-Specific Manner

“…Furthermore, HPV infections remain extremely common. Thus, there remains an urgent need to develop therapeutic HPV vaccines (Depuydt et al, 2016; Stanley, 2016). Cancer immunotherapy has emerged as an alternative, innovative approach that can induce the persistent cell-mediated immunity necessary to retard tumor growth.…”