Immune evasion by adenovirus E3 proteins: exploitation of intracellular trafficking pathways.

Adenoviruses (Ads) are nonenveloped viruses which replicate and assemble in the nucleus. Therefore, viral membrane proteins are not directly required for their multiplication. Yet, all human Ads encode integral membrane proteins in the early transcription unit 3 (E3). Previous studies on subgenus C Ads demonstrated that most E3 proteins exhibit immunomodulatory functions. In this review we focus on the E3 membrane proteins, which appear to be primarily devoted to remove critical recognition structures for the host immune system from the cell surface. The molecular mechanism for removal depends on the E3 protein involved: E3/19K prevents expression of newly synthesized MHC molecules by inhibition of ER export, whereas E3/10.4-14.5K down-regulate apoptosis receptors by rerouting them into lysosomes. The viral proteins mediating these processes contain typical transport motifs, such as KKXX, YXXphi, or LL. E3/49K, another recently discovered E3 protein, may require such motifs to reach a processing compartment essential for its presumed immunomodulatory activity. Thus, E3 membrane proteins exploit the intracellular trafficking machinery for immune evasion. Conspicuously, many E3 membrane proteins from Ads other than subgenus C also contain putative transport motifs. Close inspection of surrounding amino acids suggests that many of these are likely to be functional. Therefore, Ads might harbor more E3 proteins that exploit intracellular trafficking pathways as a means to manipulate immunologically important key molecules. Differential expression of such functions by Ads of different subgenera may contribute to their differential pathogenesis. Thus, an unexpected link emerges between viral manipulation of intracellular transport pathways and immune evasion.

Subversion of host defense mechanisms by adenoviruses.

Adenoviruses (Ads) cause acute and persistent infections. Alike the much more complex herpesviruses, Ads encode numerous immunomodulatory functions. About a third of the viral genome is devoted to counteract both the innate and the adaptive antiviral immune response. Immediately upon infection, E1A blocks interferon-induced gene expression and the VA-RNA inhibits interferon-induced PKR activity. At the same time, E1A reprograms the cell for DNA synthesis and induces the intrinsic cellular apoptosis program that is interrupted by E1B/19K and E1B/55K proteins, the latter inhibits p53-mediated apoptosis. Most other viral stealth functions are encoded by a separate transcription units, E3. Several E3 products prevent death receptor-mediated apoptosis. E3/14.7K seems to interfere with the cytolytic and pro-inflammatory activities of TNF while E3/10.4K and 14.5K proteins remove Fas and TRAIL receptors from the cell surface by inducing their degradation in lysosomes. These and other functions that may afect granule-mediated cell death might drastically limit lysis by NK cells and cytotoxic T cells (CTL). Moreover, Ads interfere with recognition of infected cell by CTL. The paradigmatic E3/19K protein subverts antigen presentation by MHC class I molecules by inhibiting their transport to the cell surface. In concert, these viral countermeasures ensure prolonged survival in the infected host and, as a consequence, facilitate transmission. Elucidating the molecular mechanisms of Ad-mediated immune evasion has stimulated corresponding research on other viruses. This knowledge will also be instrumental for designing better vectors for gene therapy and vaccination, and may lead to a more rational treatment of life-threatening Ad infections, e.g. in transplantation patients.