Manipulation of MHC class I antigen presentation by human cytomegalovirus-encoded US proteins

Successful infection of the human host is dependent on the ability of a virus to establish replication in the face of antiviral immune defenses. The genomes of the most successful human pathogens encode for gene products that disarm multiple facets of immune recognition, allowing these pathogens to flourish even as immune responses endanger their survival. Members of the Herpesviridae family are particularly adept at avoiding immune detection and elimination. The human cytomegalovirus (HCMV), the prototypic member of the beta-herpesvirinae subgroup, has committed a remarkably large percentage of its genomic coding capacity to compromising host antiviral defenses. A major target of these immunomodulating tactics is the intracellular pathway of antigen presentation by major histocompatibility complex (MHC) class I molecules. The unique short (US) region of the HCMV genome encodes for a variety of immune evasion molecules dedicated to interference with MHC class I cell surface expression, thus assuring that the virus is masked from CD8+ T-lymphocytes throughout its replication cycle.;HCMV US2 and US11 exploit a cellular process known as endoplasmic reticulum (ER) quality control in order to modulate the surface expression of MHC class I molecules. This endogenous pathway targets terminally misfolded proteins for export from the ER to the cytosol, where, by the addition of ubiquitin moieties, they are targeted for proteasomal-dependent degradation. In a similar series of reactions, both HCMV US2 and US11 induce class I heavy chain extraction from the ER membrane and deposition in the cytosol by a process referred to as dislocation. Understanding the mechanism of action of these viral proteins can offer insight into how the virus manipulates host immune responses and establishes persistence, as well as how the cell targets and disposes of proteins that fail ER quality control. It appears that HCMV US2 requires key structural features to drive the removal of class I from the ER. Mutagenesis analysis of both the US2 cytoplasmic tail and transmembrane domain demonstrated not only residues that facilitate dislocation, but also that these two structures likely work in concert to initiate extraction of class I heavy chains. US2 has been demonstrated to appropriate cellular proteins such as signal peptide peptidase (SPP) and Nedd4 for successful down-regulation of MHC class I molecules. Finally, the US3 gene product was shown to regulate class I degradation early in infection -- expression of US3 augmented US2-mediated class I degradation while, paradoxically, inhibiting the activity of US11. The data provides a more comprehensive model as to how the US genes interact with and promote the down-regulation of MHC class I molecules and sheds light on how the virus masks itself from the host immune system early during infection, a critical time of establishment and viral proliferation.