Elucidating the molecular mechanisms of MxB-mediated restriction of herpes virus infections

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Herpes viruses cause severe to life-threatening diseases, especially in patients with deficient immune responses, for example after transplantation, with AIDS or by genetic disposition. These include encephalitis and meningitis (HSV-1, HSV-2), shingles (herpes zoster, VZV), birth defects (HCMV) and cancers (EBV, KSHV). The innate immune system can limit productive herpesvirus infections. Although interferon-inducible proteins inhibit the infection at multiple sites, herpesviruses in turn antagonize these immune responses. In view of these diverse viral evasion mechanisms, the host proteins effective against herpesviruses are still poorly understood.The Kochs team has recently shown that the interferon-inducible human MxB protein encoded by the MX2 gene confines infections of alpha, beta and gamma herpesviruses. MxB is a dynamin-like, large GTPase that has already been described to be a restriction factor of HIV-1. Our previous studies show that MxB blocks viral replication early in the infection cycle, that MxB can destroy herpesviral capsids, and that MxB attacks herpesviruses by a different mechanism than HIV-1. The aim of our project is the elucidation of the molecular mechanisms of MxB-mediated antiviral activity against herpesviruses.We will compare the restriction of different human and animal herpes viruses by MxB proteins from different species to gain insights into a possible selection pressure of herpesvirus infections on the evolution of MX2 genes. We will determine how MxB prevents incoming viral capsids from releasing their genomes into the nucleus for replication, and whether MxB attacks newly assembled capsids too. With a biochemical assay, we will identify the molecular determinants of MxB that are necessary for the recognition and possible destruction of viral capsids. Furthermore, through modern protein interaction analyses, we will identify viral proteins to which MxB binds. Finally, we want to check whether MxB breaks up capsids not only in vitro but also in infected cells and thus contributes to the cytoplasmic sensing of the viral DNA. With our studies, we will determine the fate of viral capsid proteins and viral genomes in MxB-expressing cells and elucidate the molecular mechanisms of this broadly-acting intracellular restriction factor. By combining our expertise in the field of Mx-GTPases (AG Kochs) and cell biology of herpesvirus infection (AG Sodeik), we have optimal conditions to elucidate the mechanisms of MxB action against herpesviruses. We hope to contribute our findings to the development of new approaches for the treatment of life-threatening herpesvirus infections.