May 13: Viral evasion of the MHC class I antigen presentation pathway
Herpesviruses use a broad set of immune modulating mechanisms to escape the immune system, causing lifelong infections with these viruses. Human herpesviruses are associated with a wide variety of diseases. In this ‘digital I&I PhD defense’, Patrique Praest (Department of Medical Microbiology) presented newly identified interactions between viral evasins and host proteins and tried to understand how these evasins influence essential processes in the host.
Primary infections with herpesviruses are usually asymptomatic and often unnoticed in healthy individuals. However, reactivation in healthy individuals and infections in immunocompromised people can lead to serious illness (encephalitis, meningitis, neonatal herpes, disseminated infection and malignancies).
Viral evasion
The long-term co-evolution of herpesviruses and their hosts has resulted in a large number of viral proteins that act as “immune evaders”. The ‘transporter associated with antigen processing’ (TAP) is often a target of viral evasion strategies. This transporter plays a critical role in loading viral peptides onto major histocompatibility complex (MHC) class I molecules. These MHC class I molecules present peptides to cytotoxic T lymphocytes; if these cells recognize a virus-encoded peptide, they will clear the virus-infected cell. Different TAP variants exist in the human population. Some variants have previously been linked to autoimmune diseases and susceptibility to infections. The results in this thesis suggest that TAP polymorphisms have no or limited effect on peptide transport or MHC class I expression. In addition, the study indicates that the herpes virus-encoded TAP inhibitors target a broad spectrum of TAP variants; inhibition of TAP is unaffected by the polymorphisms of TAP tested in this study. Based on these findings, one could speculate about (the lack of) a contribution of herpes viruses to the selection of TAP variants during the long-term co-evolution of these viruses with their host. Structural studies pave the road to elucidate the exact mode of action of these viral TAP inhibitors and the foundation for such studies was laid in this thesis.
Broad spectrum antiviral peptide
Praest also describes a peptide derived from the cowpox virus protein CPXV012 that acts as a broad-spectrum antiviral peptide. The study described in his thesis indicates that this CPXV012 peptide hampers infection by a variety of viruses, including poxviruses, herpes simplex virus-1, hepatitis B virus, human immunodeficiency viruses, and Rift Valley fever virus. The common feature of these viruses is the presence of a mantle, the so-called envelope. Infections by uncoated viruses, such as the Coxsackie B3 virus and adenovirus, are not affected. The results indicate that direct interactions with the CPXV012 peptide can neutralize the viral particles. In addition, it was suggested that the CPXV012 peptide can inhibit viral infections through direct interactions with phosphatidylserine in the viral envelope. These results demonstrate the potential of cationic peptides as broad-acting virus inhibitors.
PhD defense
Patrique Praest (1991, Bocholt, Germany) obtained his PhD on May 13, 2020 at Utrecht University. His dissertation was titled “Viral evasion of MHC class I antigen presentation pathway”. Supervisor was prof. Emmanuel Wiertz; co-supervisor was dr. Robert-Jan Lebbink (both Department of Medical Microbiology, UMC Utrecht).