Amy Hudson, PhD
Microbiology and Molecular Genetics
Medical College of Wisconsin
Research Focus: Viral Immune Evasion
PhD: Harvard University (1995) Biological and Biomedical Sciences
We are interested in how viruses escape detection by the immune system.
As a response to selective pressures exerted by the host immune system, many viruses have developed an equally complex set of immunoevasive strategies. Perhaps most interesting is the array of unique strategies that viruses employ to interfere with the presentation of viral antigens on the surface of host cells for recognition by cytotoxic T lymphocytes.
Many viruses, including all known members of the Herpesvirus family, target antigen presentation by class I MHC molecules as a means of undermining the anti-viral immune response. We focus on two recently discovered human herpesviruses, HHV-6 and -7. Little is known about the immunobiology of these two beta-herpesviruses. They are most closely related to human cytomegalovirus (HCMV), and like all other herpesviruses, HHV-6 and -7 remain latent or establish persistent infections. Thus, it seemed likely that HHV-6 and -7 would also encode unique mechanisms of immune evasion. Because so many of the viral immunoevasins affect trafficking or stability of class I MHC molecules, we took a biochemical approach to examine the maturation and stability of class I molecules in HHV-7-infected T cells.
We found that class I MHC stability was indeed decreased in HHV-7-infected T cells, and that a 55 kDa viral glycoprotein co-immunoprecipitated with class I MHC molecules. We identified this associated protein as the product of the HHV-7 U21 open reading frame. U21 binds to newly-synthesized, properly-folded MHC class I molecules in the ER, shortly after synthesis. Expression of U21 in cultured cells results in a reduction of class I molecules on the plasma membrane and a dramatic redistribution of class I molecules to lysosomes.
Targeting of a protein to the lysosomal compartment is generally accomplished through association of cellular sorting machinery with a sorting motif contained within its cytoplasmic tail. Surprisingly, however, even expression of a tailless U21 can divert class I MHC molecules to lysosomes. Thus it is the lumenal domain of U21 that is responsible for diverting class I molecules to lysosomes. To our knowledge, this is the first description of a lysosomal targeting signal contained within a lumenal domain of a transmembrane protein. This implies that there is a currently unidentified cellular mechanism for lysosomal sorting.
How does the lumenal domain of U21 divert class I MHC molecules, and what is the cellular mechanism for lysosomal sorting that U21 harnesses for its benefit? We focus on characterizing this novel immunoevasive strategy as a means of dissecting the underlying cell biology behind this lysosomal sorting mechanism.