We are studying viral proteins which disrupt the assembly and/or trafficking of class I major histocompatibility complex (MHC) molecules. The immune response to viral infections depends heavily on the ability of class I molecules to present viral antigens to CD8-positive, cytolytic T cells (CTL.) Viruses which can prevent class I expression may be able to escape the CTL response and establish a persistent infection. Adenovirus, herpes simplex virus, and human cytomegalovirus (HCMV) have all been found to down-regulate the expression of class I MHC molecules. The clinical relevance of class I down-regulation is evident as all three of these viruses are able to establish a long-term nfection in the host.
Our aims are two-fold. First we are using cell biological and biochemical techniques to more fully define the effects that adenovirus E3/19K and HCMV US3, two proteins known to disrupt class I expression, have on the assembly of class I MHC molecules. Second, we are trying to define the binding site for these viral proteins on the class I molecule. The Computer Graphics Labortory facilities are aiding us in the second aim. By aligning the sequences of class I MHC molecules which do and do not bind these viral proteins and by comparing crystal structures known for some of the class I molecules, we are trying to identify structural motifs on the class I molecules which mediate the binding of these viral proteins. The CGL facility will also allow us to do distant homology searches on these viral proteins in an attempt to identify any host homologs.
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