The ups and downs of adenovirus vectors

Abstract

Owing to the detailed knowledge of the structure of the adenovirus virions, including their DNA genomes, especially types 2 and 5, they are convenient viruses for construction of vectors for gene therapy and vaccine immunization. It is critical to note, however, that adenoviruses produce pathogenic inflammatory responses to infection. The inflammation occurs even if the adenovirus does not replicate when the inoculum is sufficiently large, because only early gene expression is responsible for the pathogenic reaction. The inflammation consists of an early phase, in which tumor necrosis factor alpha (TNF-alpha) plays a major role, and a late phase consisting of an extensive T-cell response. It is important in the construction of adenovirus vectors not to delete a major portion of the early region 3 (E3) because: the E3 19 kD glycoprotein markedly reduces the capacity of the Class I major histocompatibility complex (Class I MHC) from transporting viral antigens to the surfaces of infected cells; and the E3 14.7 kD protein significantly inhibits the production of TNF-alpha and, therefore, reduces the polymorphonuclear response. Unfortunately the first generation of adenovirus gene therapy vectors contained large E3 deletions and, therefore, presented a significant safety problem. Subsequent adenovirus vectors consist of other deletions to overcome this difficulty.