What new therapeutic options open up, from research into the assembly process of herpesviruses

What is this research project about?

HSV1 (red) in nerve cells (tubulin in blue)

What is this research project about?

While a healthy immune system is able to control herpesviruses, primary and recurrent infections can cause severe disease; particularly very early in life and in the elderly as well as in individuals with increased susceptibility, either due to genetic factors or to immune suppression, e.g., after organ transplantation or for those living with HIV/AIDS. Due to their ubiquitous prevalence, the disease burden of herpesviruses is high in industrialized and developing countries. Diseases range from stigmatizing skin lesions to unbearable pain, life-threatening encephalitis and cancers. The human herpesviruses responsible for the most serious and even life-threatening complications are human cytomegalovirus (HCMV), Herpes Simplex virus (HSV-1 and HSV-2), Varicella Zoster Virus (VZV), and Kaposi Sarcoma Herpesvirus (KSHV).

What’s the current status?

Only few licensed drugs are in clinical use to treat herpesvirus infections, and these target mainly enzymes required for viral DNA replication. Furthermore, these drugs have severe side effects, and resistant viral strains emerge upon prolonged treatment. The recently approved Letermovir that inhibits the HCMV terminase, may represent the first drug to expand our scope of antiviral targets. However, first resistant HCMV mutants have already been described indicating that combination therapies – as used successfully against HIV and HCV – are required. To this end, our research aims at the identification and characterization of unique protein-protein interactions that are essential for virion assembly and therefore potentially represent novel druggable targets. This strategy will pave the way for advanced combination therapies with reduced side effects, and a much lower risk of the emergence of drug-resistant viruses in patients.

What are the project goals?

The major aims of this project are to characterize novel molecular mechanisms and protein-protein interactions that are key for herpesvirus assembly. The latter is a complex and highly regulated process including nuclear capsid assembly and genome packaging, nuclear egress, tegumentation in the cytoplasm, and capsid envelopment on cytoplasmic organelles. Each of these steps relies on essential, highly conserved, multimeric protein-protein interactions. Herpesvirus capsids assemble in the nucleus followed by genome packaging – a process mediated by a viral ternary protein complex called “terminase”. Subsequently, the mature capsids exit the nucleus via a specific nuclear escape mechanism that is driven by a viral protein complex called “nuclear egress complex”. Interactions of inner tegument proteins with the host cell’s microtubule transport machinery facilitate capsid transport to the site of final envelopment. We aim to synergize our diverse expertise on herpesvirus cell biology, protein functions, and structure to identify crucial protein-protein interactions that provide unique targets for novel anti-herpesviral therapy.

How do we get there?

We will focus on elucidating the underlying molecular principles how evolutionary conserved protein complexes function in herpesvirus assembly, and unite our unique expertise on crucial steps of herpesviral assembly (in collaboration with Thomas Schulz and Abel Viejo Borbolla). Combined, we have profound experience on sophisticated protein expression strategies, state-of-the-art structural biology (including X-ray crystallography, cryo electron microscopy, and electron cryo tomography), protein biochemistry (e.g. label-free interaction analysis, co-immuno-precipitation, in vitro capsid assembly and tegumentation), herpesvirus genetics (BAC mutagenesis), immunoelectron microscopy of infected cells and tissues, and life cell imaging using strains with fluorescently tagged capsids and tegument. With our broad expertise, we will uncover evolutionarily conserved mechanisms as well as steps that diverge in virus assembly among different herpesviruses.

Projectleaders D2

Project title: Herpesviral assembly

Prof. Dr. Kay Grünewald

Projekte: D1, D2

Prof. Dr. Thomas Krey

Projekte: B10, D1

Prof. Dr. Martin Messerle

Projekte: D1, D2

Prof. Dr. Beate Sodeik

Projekte: A4, D1, D2

Project D2 Publications

Publications 2022

The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses eLife. Manutea C Serrero, Virginie Girault, Sebastian Weigang, Todd M Greco, Ana Ramos Nascimento, Fenja Anderson, Antonio Piras, Ana Hickford Martinez, Jonny Hertzog, Anne Binz, Anja Pohlmann, Ute Prank, Jan Rehwinkel, Rudolf Bauerfeind, Ileana M Cristea, Andreas Pichlmair, Georg Kochs, Beate Sodeik (2022). eLife

Publications 2021

Assembly of infectious Kaposi’s sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer. Naniima P, Naimo E, Koch S, Curth U, Alkharsah KR, Ströh LJ, Binz A, Beneke JM, Vollmer B, Böning H, Borst EM, Desai P, Bohne J, Messerle M, Bauerfeind R, Legrand P, Sodeik B, Schulz TF, Krey T. PLoS Biol. 2021 Nov 4;19(11):e3001423.

Infection-induced chromatin modifications facilitate translocation of herpes simplex virus capsids to the inner nuclear membrane. Aho V, Salminen S, Mattola S, Gupta A, Flomm F, Sodeik B, Bosse JB, Vihinen-Ranta M.PLoS Pathog. 2021 Dec 15;17(12):e1010132.

Concatemeric Broccoli reduces mRNA stability and induces aggregates. Rink MR, Baptista MAP, Flomm FJ, Hennig T, Whisnant AW, Wolf N, Seibel J, Dölken L, Bosse JB. PLoS One. 2021 Aug 4;16(8):e0244166.  eCollection 2021.

Publications 2020

The prefusion structure of herpes simplex virus glycoprotein B. Vollmer B, Pražák V, Vasishtan D, Jefferys EE, Hernandez-Duran A, Vallbracht M, Klupp BG, Mettenleiter TC, Backovic M, Rey FA, Topf M, Grünewald K.  Sci Adv. 2020 Sep 25;6(39):eabc1726.

A molecular pore spans the double membrane of the coronavirus replication organelle. Wolff G, Limpens RWAL, Zevenhoven-Dobbe JC, Laugks U, Zheng S, de Jong AWM, Koning RI, Agard DA, Grünewald K, Koster AJ, Snijder EJ, Bárcena M. Science. 2020 Sep 11;369(6509):1395-1398. doi: 10.1126/science.abd3629. Epub 2020 Aug 6.

Publications 2019

Quantitative Microscopy Reveals Stepwise Alteration of Chromatin Structure during Herpesvirus Infection. Aho V, Mäntylä E, Ekman A, Hakanen S, Mattola S, Chen JH, Weinhardt V, Ruokolainen V, Sodeik B, Larabell C, Vihinen-Ranta M. Viruses. 2019 Oct 11;11(10):935. doi: 10.3390/v11100935. PMID: 31614678; PMCID: PMC6832731.

Publications of the Project D2