Structure and Function of Viral Immunoevasins

National Institute Of Allergy And Infectious Diseases

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Abstract

The focus of this work has been to understand the molecular details that control initial steps in the recognition of cells infected with pathogens such as viruses by cells of the innate and adaptive immune systems. Understanding the function, mechanism, structure, and evolution of the interaction of virus-encoded molecules recognized by the immune system can lead not only to a deeper understanding of molecular interactions in general and of cell-cell interactions in the immune system, but also may lead to rational approaches to intervention in virus infection and neoplasia. In particular, we study representative members of the large family of major histocompatibility complex (MHC)-encoded molecules from a biophysical and structural perspective. We are interested in how MHC-I molecules interact with receptors on natural killer (NK) cells and on T lymphocytes through their NK and T cell receptors, respectively. Large DNA viruses of the herpesvirus family produce proteins that mimic host MHC-I molecules as part of their immunoevasive strategy, and we have directed our efforts to understand the function, cellular expression, and structure of a set of these MHC-I (referred to as MHC-Iv) molecules encoded by the mouse cytomegalovirus (mCMV). We have analyzed the expression and binding of several members of the MHC-Iv family, in particular the molecules, m144, m152, and m153. In earlier studies, we determined the structures of the MHC-Iv molecules, m144, m152, and m153. Recent experiments from other labs have identified a novel immunoevasin encoded by the Molluscum contagiosum virus, MC80, that impedes antigen presentation by interacting with tapasin in the protein loading complex, and directs tapasin to an endoplasmic reticulum degradative pathway. We have expressed and purified a recombinant form of the MC80 protein for structural and binding studies, and expect that the basic knowledge gained will enhance our understanding of the MHC peptide loading pathway.