Download Viral Gene Transfer Vectors Summary by John T. Gray, PhD Host

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.