Our laboratory studies the interactions between viruses and the hosts they infect, focusing on the mechanisms by which HPV 16, a virus that causes cervical carcinoma, avoids elimination by the host immune system. Papillomavirus infections typically result in little or no immune activation, and thus the virus can persist in the host for long periods of time. Our laboratory has shown that the viral E6 oncoprotein is responsible for much of this immune evasion. E6 functions, at least in part, by protecting the cells that express it from host-generated apoptotic responses such as those triggered by TNF, Fas and TRAIL. Each of these apoptotic pathways involves several signaling molecules, and E6 works by binding to some, though not all, of them. One possible consequence of such binding is the blocking of signal transmission, such as we observed following the binding of E6 to the TNF receptor TNF R1. This prevents TNF R1 from binding to the next molecule in the pathway, TRADD. Another possible consequence is the degradation of signaling intermediates, noted following the binding of E6 to FADD or to procaspase 8. We are working to further define these interactions with a long-term goal of developing small molecule inhibitors of such binding, which would have the potential to function as therapeutic reagents.
Interestingly, E6 occurs in two versions due to alternative splicing. These two splicing variants offer the virus additional diversity in immune evasion mechanisms. For example, while the full-length version is required to protect cells from apoptosis triggered through Fas, both the truncated and the full-length versions can provide protection from TNF. Also, while both versions bind to procaspase 8, only the full-length version accelerates its degradation.
Finally, we have used microarray analysis to discover that E6 affects the cellular responses to apoptotic signals induced by DNA damage by changing the expression patterns of genes involved in the early response, and these studies have identified a number of potential new targets for the development of chemotherapeutic reagents. Together, our results indicate that HPV 16 has acquired a number of mechanisms designed to thwart host-triggered apoptosis and to ensure the survival of the virus and its host cell. A clear understanding of these host-virus interactions will facilitate efforts to develop novel and effective therapeutic approaches.