Work in the Gooding laboratory focuses on the interactions between infectious viruses and host immune defense mechanisms. It is becoming evident that the same evolutionary pressures that forced the development of anti-viral immune mechanisms in vertebrates also induced the DNA viruses to develop countermeasures that render host defense ineffective. Gooding and co-workers have described several such countermeasures in human group C adenoviruses that protect the virus-infected cell from destruction by host cytokines (notably TNF) and from lysis by anti-viral cytotoxic T cells or natural killer cells. Current work in the laboratory includes identification of additional adenoviral genes that counteract host defenses, discovery of the molecular mechanisms by which the viral proteins function, and mutation of viral genes as a probe for understanding the virus/host interface in vivo. This latter goal is especially important because viral pathogenesis is often caused not only by the virus itself, but by over-responses of host defenses leading to tissue damage.

Currently this group is investigating the mechanisms of adenovirus persistence in human tonsil and adenoid tissues. Adenoviral DNA is found in mucosal lymphoid tissues in most children. This DNA is located selectively in T lymphocytes, suggesting a possible latency mechanism. Current investigation focuses on identifying which T cell subsets harbor the virus and determining what signals lead to reactivation of viral replication in vitro. In addition, the group has established a model system in a human T lymphocyte cell line that mimics the behavior of the virus in tonsil T cells. This model will facilitate detailed analysis of the atypical virus life cycle that permits long-term association of the virus with T lymphocytes in vivo. One current hypothesis is that viral genes responsible for neutralizing host defense are uniquely regulated and act to protect the persistently infected T cell from destruction. Thus, virus persistence requires expression of at least some members of this class of viral genes.

Overall, it is anticipated that this work will contribute to a variety of different approaches to human disease from the development of viral vaccines, where genes that interfere with vaccine effectiveness will be identified and deleted from the immunizing strain, to the use of adenovirus as a vector for gene transfer, where viral genes that dampen host responsiveness will be expressed at high levels to prevent elimination of the transferred gene. In addition, the finding of adenovirus, with its known capacity for mutagenesis, in T cells that continue to divide provides strong incentive to reevaluate the real-life oncogenic potential of this DNA "tumor" virus.

[gooding@microbio.emory.edu]