Quantitative human papillomavirus 16 and 18 levels in incident infections and cervical lesion development

Abstract

Human papillomavirus (HPV) RNA levels may be a more sensitive early indicator of predisposition to carcinogenesis than DNA levels. We evaluated whether levels of HPV-16 and HPV-18 DNA and messenger RNA (mRNA) in newly detected infections are associated with cervical lesion development. Female university students were recruited from 1990-2004. Cervical samples for HPV DNA, HPV mRNA, and Papanicolaou testing were collected tri-annually, and women were referred for colposcopically-directed biopsy when indicated. Quantitative real-time polymerase chain reaction of L1 and E7 DNA and E7 mRNA was performed on samples from women with HPV-16 and HPV-18 infections that were incidently detected by consensus PCR. Adjusting for other HPV types, increasing E7 cervical HPV-16 mRNA levels at the time of incident HPV-16 DNA detection were associated with an increased risk of cervical intraepithelial neoplasia grade 2 to 3 (HR per 1 log10 increase in mRNA=6.36,95%CI=2.00-20.23). Increasing HPV-16 mRNA levels were also associated with an increased risk of cervical squamous intraepithelial lesions; the risk was highest at the incident positive visit and decreased over time. Neither HPV-16 E7 DNA levels nor HPV-18 E7 DNA nor mRNA levels were significantly associated with cervical lesion development. Report of >1 new partner in the past 8 months (relative to no new partners) was associated with increased HPV mRNA (viral level ratio [VLR]=10.05,95%CI=1.09-92.56) and increased HPV DNA (VLR=16.80,95%CI=1.46-193.01). In newly detected HPV-16 infections, increasing levels of E7 mRNA appear to be associated with an increased risk of developing cervical pre-cancer.

Early Natural History of Incident, Type-Specific Human Papillomavirus Infections in Newly Sexually Active Young Women

“…We previously showed that report of more than one new partner in the eight months prior to incident HPV-16 or HPV-18 infection was associated with increased E7 mRNA viral levels (9) (and higher viral levels have been linked with persistent detection (10–12)). No statistically significant sexual behavioral determinants of persistent versus transient infections were identified.…”

Is Human Papillomavirus Viral Load a Clinically Useful Predictive Marker? A Longitudinal Study

“…Finally, it must be remembered that viral replication is not necessary for maintaining the malignant phenotype. In situ assays on cervical cancer cell lines have found that not all HPV copies are transcriptionally active; in women with incident HPV16 infections, HPV E7 mRNA levels, but not viral load, are associated with an increased risk of developing squamous intraepithelial lesions (13,14). Robust measurements of type-specific viral load in samples in which integration status and the expression of viral oncogenes are also defined will continue to provide useful insights into the pathogenesis of HPV-associated disease.…”

Koilocytes indicate a role for human papilloma virus in breast cancer

“…Increasing levels of HPV viral load seem to be associated with an increased risk of developing cervical pre-cancer (Winer et al, 2009). This is relevant to HPV-associated breast cancer as the viral load in cervical cancer seems to be over 4000 times higher than in breast cancer (Fiander et al, 2007;Khan et al, 2008).…”