Host cell reprogramming by oncogenic human papillomavirus

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Viral infections are estimated to cause over 1 in 10 of all cancers, resulting in over 1.3 million deaths a year, worldwide. One of the most significant contributors to this virally-induced cancer burden are human papillomaviruses (HPV); HPV infections cause almost half of these cancers, including cancers of the uterine cervix and genitals, and oral cancers in the mouth and throat. While the causal link between HPV and the development of cancer is well established, the specific changes that occur in HPV infections that drive the formation of HPV tumours are not well understood. It is important to understand these changes so that new therapies to treat HPV infections and cancers, and diagnostic tools for early disease detection, can be developed. There are hundreds of distinct types of HPV, but only a very small number of these are classified by the World Health Organisation as carcinogenic. HPV type 16 causes the majority of cervical and oral cancers whereas HPV type 18 is the second most common cause of cervical cancer but is rarely found in oral cancers. The reasons for this disparity are unknown but we hypothesise that HPV types 16 and 18 differentially manipulate host cells at different anatomical sites resulting in the observed differences in clinical outcome. All viruses manipulate their host cell environment to enhance production of infectious progeny. We have shown that establishment of HPV infection in the natural host cells significantly alters the expression of a subset of host cell genes. This HPV-driven gene expression 'reprogramming' is fundamental to persistence of HPV infection, a significant risk factor for cancer development. Importantly, many of the gene expression changes that occur early in the natural history of persistent HPV infections increase the growth rate and life span of the infected cells, and therefore are very likely contribute to disease progression. The experiments described in this proposal are designed to answer long-standing questions about how HPV16 and 18 behave in a normal infection of the oral cavity or uterine cervix. We will fully characterise the molecular basis of HPV-induced gene expression changes and determine which of these changes are important for viral persistence and disease progression at each body site. Using cancer cell lines and clinical samples of HPV-associated tumours, we will explore whether novel virus-specific changes are required for cancer cell growth and sustained in HPV-driven tumours. These experiments will provide much needed novel insight into the normal life cycle of HPV infections at clinically relevant body sites and identify virus-specific events that drive disease progression.