Regulation of Human Papillomavirus Type 16 Late L1 mRNA Splicing

Sammanfattning: Popular Abstract in English Each year an estimated 530 000 new cases of cervical cancer are diagnosed and more than 275 000 women die from cervical cancer worldwide (2). Cervical cancer is caused by sexually-acquired infections with a subset of human papillomavirus (HPV) (359, 360). HPV is the most common viral infection of the anogenital tract (2). Almost all sexually active individuals will be infected by HPV at least once but probably multiple times during their lives. Most HPV infections do not cause any symptoms or disease as they spontaneously resolve, often within one to two years after infection. However, infections with specific types of HPVs (most frequently type 16 and 18) may persist and lead to precancerous lesions or cancer if they are not appropriately treated. More than 40 types of HPVs are sexually transmitted and infect the anogenital region. HPV types that infect the genital mucosa are divided into two groups: High-risk (HR) types like HPV-16, 18, 31 and 33 that can cause genital, mouth, or oro-pharynx cancer, and low-risk (LR) types like HPV-6 and 11 that may cause warts, but are not found in malignancies. HR HPV-16 and 18 are the most frequently detected HPV types in cervical cancer (244). Although vaccines against HR HPV-16 and 18, and LR HPV-6 and 11, are available nowadays, there is a large number of new cases of cervical cancer and deaths each year, especially in low and middle income countries (2). Vaccination is only freely available for girls aged 9-13 years in a few developed countries. Papanicolaou test and liquid-based cytology are two available methods in cervical cancer screening (44, 247). However, there are no efficient biomarkers or medicines available for diagnostic or treatment of HPV infections at risk of progressing to cancer. Therefore, it is important to fully understand the mechanism of HPV persistence in order to uncover novel biomarkers for disease, or targets for antiviral treatment. In this study, we have investigated how HPV-16 late gene expression is regulated at the level of RNA processing. These results will enhance our understanding of the ability of HPV-16 to hide from the immune system by using a highly regulated gene expression program. This is highly significant since establishment of HPV-16 persistence is one of the most important risk-factors for development of cervical cancer.