E1A and E1B proteins inhibit inflammation induced by adenovirus

Abstract

Replication-defective human adenovirus (Ad) group C transducing vectors, most of which have the E1A, E1B, and E3 genes deleted, are highly inflammatory despite the fact that the parental viruses typically cause subclinical or mild infections. To investigate this paradox, the roles that the E1A, E1B, and E3 genes play in inflammation were tested by using replication-incompetent viruses carrying a deletion of the preterminal protein gene. The viruses were injected into BALB͞c mouse ears, and edema was monitored as a sensitive surrogate marker of inflammation. A virus deleted for the E1A 289R (transcription activating) protein was noninflammatory, and inhibited edema induced by empty virus particles. The E1A 243R and E1B 55-kDa (p53 binding) proteins play the most important roles in inhibition of inflammation by the noninflammatory virus. The E1B 19-kDa antiapoptotic protein inhibited edema when both the E1A 243R and E1B 55-kDa proteins were expressed but strongly induced edema when only one was expressed. E3 proteins had their greatest effect on the inhibition of edema induced by the E1A 289R protein. The results support a model in which inflammation is countered through a mechanism that involves complex genetic interactions between Ad early region proteins and offer promise for the design and construction of noninflammatory Ad gene therapy vectors that are relatively easy to grow and purify.

Intrinsic Structural Disorder in Adenovirus E1A: a Viral Molecular Hub Linking Multiple Diverse Processes

“…It also reprograms host cell gene expression, forcing quiescent cells to enter and pass through the cell cycle, blocking cell differentiation (7,8,34,38). E1A also plays a role in suppressing the inflammatory response to the viral infection (113). HAdV infection of human cells is lytic, usually resulting in the death of the host cell and the release of progeny virus.…”

Downregulation of Varicella-Zoster Virus (VZV) Immediate-Early ORF62 Transcription by VZV ORF63 Correlates with Virus Replication In Vitro and with Latency

“…VZV ROka (recombinant Oka), ROka63D (5), ROka63-AccI, ROka-63-5M, and ROka63-KpnI (6) were grown in human melanoma (MeWo) cells by cocultivation of infected and uninfected cells. Recombinant adenoviruses Ad63, expressing ORF63 and green fluorescent protein (GFP), and Adblank, expressing GFP alone, were constructed as described previously (17), with modifications (40,48). All adenovirus constructs were grown in human kidney epithelial 293 cells.…”

Adenoviral vector saturates Akt pro-survival signaling and blocks insulin-mediated rescue of tumor-necrosis-factor-induced apoptosis

“…Resident macrophages efficiently take up Advs and then release TNF within the tissue to eliminate infected cells (Lieber et al, 1998;Lieber et al, 1997). Wild-type E1 and E3 adenoviral early proteins are known to manipulate cell responses to TNF-family cytokines (Benedict et al, 2001;Duerksen-Hughes et al, 1989;Rao et al, 1992;Schaack et al, 2004). Adenoviruses normally use these E1/E3-mediated mechanisms to promote cell survival long enough to complete the viral replication cycle.…”