Much of the research in the Ploegh lab is in the fields of biochemistry and immunology, which started with a specific focus on the unraveling the mechanisms by which MHC molecules interact with antigens inside a cell. Later, while at the Whitehead Institute, the Ploegh lab began using a technique called ‘sortagging’ to look at the pathways through which viruses are able to avoid detection by the immune system. Ploegh has been involved in further developing therapeutic roles for sortagging. Additionally, the Ploegh lab now focuses on utilizing ‘nanobodies’, derived from the antibodies of alpaca’s. Much of the research currently done in the lab uses these nanobodies for fundamental research and therapeutic applications.

Hidde Ploegh’s laboratory is interested in the biochemistry of immune recognition, and in mechanisms by which pathogens avoid being seen by the immune system. His earlier work centered on the analysis of the biochemical pathways involved in antigen processing and presentation by the products of the Major Histocompatibility Complex (MHC), which led to studies into glycoprotein biosynthesis and trafficking more generally. The discovery that human cytomegalovirus exploits an unusual mechanism to dispose of Class I MHC products, critical for recognition by cytotoxic T cells of virus-infected cells, led to observations that illuminated new aspects of glycoprotein quality control. Ploegh has applied chemistry to develop activity-based probes to study proteasomal proteolysis and more specifically the role of ubiquitin-specific proteases, also in the context of herpesvirus infections. More recently Ploegh has combined the generation of camelid-derived antibody fragments with a protein engineering approach, based on the use of bacterial sortases in conjunction with peptide chemistry. This combination is being developed to enable the visualization, by non-invasive means, of anti-tumor and anti-virus immune responses using positron emission tomography.