Human Papillomavirus (HPV) 16/18 E6 Oncoprotein Expression in Infections with Single and Multiple Genotypes

Abstract

Factors that differentiate risk of cervical cancer associated with infection with single versus multiple HPV types are yet undefined. We hypothesize that E6 oncoprotein is one determining factor. This cross-sectional, multicenter study was performed between 2013 and 2017. A total of 1,781 women were recruited from six hospitals. Samples were tested for presence of 14 types of high-risk HPV DNA. HPV16/18-positive samples were also tested for HPV16/18-E6 oncoprotein. Of 1,781 subjects, 687 (38.6%) tested positive for HPV16/18. HPV16/18 single infections were associated with higher E6 positivity rates compared with multiple infections only for cancer cases (HPV16: 92.2% vs. 76.5%; HPV18: 93.9% vs. 62.1%) but not for normal histopathology or cervical intraepithelial neoplasia. In HPV16/18 coinfection subjects, the positivity rate was 42.9% for HPV16-E6 and 42.9% for HPV18-E6. The combined positivity rate of either HPV16-E6 or HPV18-E6 among HPV16/18 coinfection subjects was 78.6%, similar with HPV16 (74.8%) and HPV18 (79.5%) single-infection subjects. The positivity rates of HPV16/18 E6 oncoprotein varied depending on the HPV-type composition in multiple infection ("clusters") including HPV types other than 16 and 18. Multiple infection clusters most likely to express HPV16-E6 and HPV18-E6 were HPV16/52 (61.5%) and HPV18/52 (66.7%), and the less were HPV16/45 (10.0%) and HPV18/51 (16.7%), respectively. Patterns of E6 oncoprotein expression varied depending on clustering types. However, expression was greatest in women with single HPV-type infections compared with those with multiple HPV types regardless of histopathology. Our findings provided new insight of natural history of cervical cancer.

Higher clearance rates of multiple HPV infections may explain their lower risk of HSIL: A retrospective study in Wenzhou, China

“…While similarly to our findings, many studies have suggested that there may be antagonistic effects between HPV subtypes in multiple infections 13,26,27 . Xi et al found that HPV16 DNA viral load was significantly lower in multiple infections with HPV α9 type and tended to decrease significantly with increasing number of HPV genotypes.…”

“…Under the assumption of independent infection with each genotype of HPV, multiple infections occur more frequently than expected, 12 accounting for approximately 20%–50% of HPV‐positive patients 9,10,13‐15 . The proportion of multiple HPV infections found in invasive cervical cancer has increased substantially over the last two decades, from 4.0% to 15.7%, despite the fact that cervical cancer is a monoclonal disease caused by only one HPV type.…”

“…Several studies have found that multiple HPV infections result in a significantly higher risk of cervical lesions compared to single HPV infections, 16‐19 and even their incidence is consistent with the degree of cervical lesions 18 . Explanations for this existence include: (1) multiple infections still follow the theory of independent pathogenicity of HPV and the resulting increased risk is a mere accumulation of the risk of single HPV infections 13,16,20 . Therefore, no interaction exists between the different type of HPV; 12 (2) there is a possible link between HPV multiple infections and persistent HPV infection due to the synergistic effect between different HPV infection subtypes, 19,21 which in turn causes more severe cervical lesions.…”

Clustering patterns of type‐type combination in multiple genotypes infections of human papillomavirus in cervical adenocarcinoma

“…Significantly lower HPV 16 and HPV 18 viral loads among the women coinfected with phylogenetically‐related HPV types have been found . More recently, Wu et al found that HPV clustering types were associated with patterns of E6 oncoprotein expression. Pimenoff et al based on a worldwide cross‐sectional study of invasive cervical cancer (mostly squamous cell carcinoma) observed the differential geographic HPVs coinfections patterns, but this correlation seems not reproducible in ADC.…”

Possible different genotypes for human papillomavirus vaccination in lower middle-income countries towards cervical cancer elimination in 2030: a cross-sectional study

“…However, there is a limited study of single and multiple HPV infections in the normal cervix population. Also, the distinguishing factors of cervical cancer risk associated with infection with one or more HPV types have not yet been defined [ 20 ]. Li et al [ 21 ] in Beijing, China, found that the incidence of CIN2+ was higher in patients with HPV 16 single infection than multiple infections of the same genotype HPV.…”