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Viral Gene Transfer Vectors Summary by John T. Gray, PhD Host Cell Responses to Viral Vectors Co-Chairs: John T. Gray, PhD and Dmitry M. Shayakhmetov, PhD The 2013 ASGCT Scientific Symposium on Host Cell Responses to Viral Vectors brought together 4 excellent speakers who covered a range of topics relating to the challenges vectors face when interacting with host tissues. Dr. Vojo Deretic first gave an introduction to the newly emerging field of autophagy, which is a homeostatic process that cells use to continuously cleanse the cytosol by removing defunct organelles, protein aggregates, microbial invaders, and endogenous sources of inflammation. Dr. Deretic described how this fundamental cellular process can interact with viruses at numerous steps of the replication cycle, and gave excellent detail about how the induction of the process in cells is typically monitored by researchers in the field. He also highlighted some of the latest developments in the study of how this process interacts with the host inflammatory response. The next presentation was by Dr. Roland Herzog, who presented his latest research in the area of innate immune responses to AAV vectors. Although AAV is known to be far less inflammatory than other vector systems, Dr. Herzog’s recent research has revealed that AAV particles can stimulate innate immune pathways (through Toll-Like Receptor 9) and that this stimulation can affect the immune response to vector particles as well as the transgene product. Dr. Herzog presented his latest data dissecting the molecular pathways responsible for the recognition of AAV and the mechanisms whereby the stimulatory signals are communicated to immune effector cells. He showed that these pathways can be influenced by the nature of the vector genome (self-complementary vs. single-stranded) and can play a strong role in the efficacy and safety of AAV vectors. John Bell presented the latest advances his team has made exploring the effect of innate immune pathways on the efficacy of oncolytic viruses developed in his laboratory. The viruses have been engineered to specifically replicate in and kill tumor cells, and although these products are showing exciting clinical efficacy, Dr. Bell’s research into the mechanism of the tumor cell killing has revealed some interesting surprises. He presented data at the symposium showing that although the disrupted cell signaling pathways in tumor cells were expected to allow selective replication of the oncolytic viruses in only those cells, it appears as though this dysregulation extends to the tumor microenvironment, and leads to the replication in and destruction of developing vascular endothelium. Thus, these oncolytic viruses mediate their effect by multiple mechanisms, including what is effectively an anti-angiogenic cell killing of developing tumor vasculature. Dmitry Shayakhmetov presented the data from a herculean effort to characterize molecular mechanisms related to the sensing of endosomal rupture, which is the process whereby cells recognize perturbations of the integrity of the endosomal compartments in the cell. These pathways can be critical for proper stimulation of innate immune recognition of viral infections, and Dr. Shayakhmetov presented his work dissecting the signaling effector molecules critical for cellular recognition of adenovirus infection and stimulation of necrotic cell death. Summarizing results of experiments in an overwhelming number of mouse strains, he showed that this pathway has some similarity to other innate immune pathways in that it is transmitted through IRF3, but does not utilize any of the previously characterized factors upstream of IRF3. A publication describing his results is now in press at Cell Reports.