Regulation of the adenovirus E3 transcription unit in human T cells

There are two phases of adenovirus replication: acute and persistent. The molecular events of the acute phase are well understood but the persistent phase remains poorly characterized and only known through epidemiological studies. Adenovirus is profoundly proinflammatory and acute replication of the virus results in the death of the host cell. These observations suggest that the virus must modify its replication strategy in order to persistent in an immunocompetent host. Recent data supports a role for tonsillar T lymphocytes as a reservoir of persistent adenovirus. The ability of the E3 transcription unit to inhibit Fas, TNFR1 TRAIL-R1 and TRAIL-R2 mediated apoptosis suggests that this transcription unit plays a role in facilitating persistent infection of T lymphocytes. Studies in this dissertation show that the E3 promoter is sensitive to T cell activation signals through its NF-κB sites. Consistent with previous research demonstrating E1A inhibition of NF-κB dependent promoter transactivation, the E1A protein is able to inhibit this activation in a transient transfection system, however we were unable to see an effect of E1A during virus infection. Infection of different T cell lines shows that while some T cell lines support full lytic viral replication, others are able to replicate the viral genome in a non-lytic manner.; TNF upregulates the expression of many different cytokines and chemokines and plays an important role in the immune response. TNF induction of IL-8, A20 and MnSOD is inhibited in wild type adenovirus infected epithelial cells. Furthermore, TNF induced degradation of IkB-α is completely blocked in these cells. Despite the presence of IkB-α, some NF-κB is able to access the nucleus and upregulate transcription from a reporter plasmid.