The life and times of adenoviruses.

With Wallace Rowe et al.'s and Hilleman and Werner's isolations of viruses, subsequently termed "adenoviruses," a new area of research opened for me and gradually for many others. I was quickly able to associate the viruses with diseases in humans, and then our attention turned to the structure of the virion and how it replicated. Many virologists entered these areas of adenovirus research, for they were the central themes for most virologists at that time. We obtained more and more knowledge of the structure of the virion, its genome, and how it replicated and killed cells in culture so that they could no longer divide, although the virus infection did not lyse the infected cells, but we did not have the slightest idea how Ad5 produced disease in vivo. Then Wallace Clyde's timely note appeared, and we entered an exciting and profitable new field: an investigation of the mechanism by which Ad5 produces pneumonia. It must again be emphasized that the pneumonia that WtAd5 produces in cotton rats is pathologically very similar to that induced in humans. One of our earliest sets of experiments in the cotton rats was designed to determine whether region E3 was really nonessential even though the genes contained therein were not required for viral replication. We soon demonstrated that deletion of the E3 region produced a mutant that induced a highly pathogenic viral pneumonia. The potential role in pathogenesis of each of the genes within the E3 region was then investigated. Of maximum importance was the finding that deletion of the 19-kDa gene near the 5' end of the region produced a severe inflammatory response. This result led to the discovery that the E3 19-kDa protein regulated expression of the MHC factor on the surface of infected cells, and deletion of this gene produced a marked increase in MHC on the surfaces of infected cells and, therefore, a marked increase in the response of cytotoxic T cells. In addition, deletion of the gene encoding the 14.7-kDa protein, which was situated at the 3' end of the E3 region, resulted in an increase in polymorphonuclear leukocytes in the inflammatory response. A number of these findings led to hypotheses that could not be tested in the cotton rat since the necessary reagents were not available. Fortunately, our findings that only early viral genes are required to produce full pathogenesis led us to test mice because we had shown in a culture of mouse cells that all of the early viral genes are expressed. The C57BL/6N mouse proved to be an excellent host in which Ad5 produced full pulmonary inflammation. Thus, it was possible to test our hypotheses and to demonstrate their validity, showing that the virus induces cytokine elaboration, as well as to demonstrate the role of cytotoxic T cells in permitting Ad5 to produce persistent infections in lymphoid cells of organs such as the adenoid, from which the first adenovirus was isolated, and which had immediately led to my interest in investigating it and helping to develop the story of adenoviruses.