Changes in the Proteome in the Development of Chronic Human Papillomavirus Infection—A Prospective Study in HIV Positive and HIV Negative Rwandan Women

SIMPLE SUMMARY: Cervical cancer is the predominant cause of female cancer deaths in Sub-Saharan Africa. Chronic infection of the uterine cervix by the human papillomavirus (HPV) is the most important factor for the development of cervical cancer. HPV screening may be used to screen out women at risk of cervical cancer; however, the majority of HPV infections will eventually heal, and at present, there are no screening methods to detect which HPV infections that will become chronic. In the present study, we followed HIV-negative and HIV-positive Rwandan women with cervical HPV infections for two years with repeated samplings from the uterine cervix. We identified protein biomarkers that correlate with the potential risk for women to develop cervical cancer. By including the identified biomarkers in cervical screening programs, we are able, potentially, to identify those women with cervical HPV infections, who should be carefully monitored in the future. ABSTRACT: Background: Effects on the proteome when a high risk (HR)-HPV infection occurs, when it is cleared and when it becomes chronic were investigated. Moreover, biomarker panels that could identify cervical risk lesions were assessed. Methods: Cytology, HPV screening and proteomics were performed on cervical samples from Rwandan HIV+ and HIV- women at baseline, at 9 months, at 18 months and at 24 months. Biological pathways were identified using the String database. Results: The most significantly affected pathway when an incident HR-HPV infection occurred was neutrophil degranulation, and vesicle-mediated transport was the most significantly affected pathway when an HR-HPV infection was cleared; protein insertion into membrane in chronic HR-HPV lesions and in lesions where HR-HPVs were cleared were compared; and cellular catabolic process in high-grade lesions was compared to that in negative lesions. A four-biomarker panel (EIF1; BLOC1S5; LIMCH1; SGTA) was identified, which was able to distinguish chronic HR-HPV lesions from cleared HR-HPV/negative lesions (sensitivity 100% and specificity 91%). Another four-biomarker panel (ERH; IGKV2-30; TMEM97; DNAJA4) was identified, which was able to distinguish high-grade lesions from low-grade/negative lesions (sensitivity 100% and specificity 81%). Conclusions: We have identified the biological pathways triggered in HR-HPV infection, when HR-HPV becomes chronic and when cervical risk lesions develop. Moreover, we have identified potential biomarkers that may help to identify women with cervical risk lesions.