How can we stop the life cycle of these pathogens at an early step?

What is this research project about?

What is this research project about?

Persistent viral infections with human herpesviruses represent a serious threat to susceptible and immunocompromised individuals like newborn babies, senior individuals, transplant recipients and persons with other immune defects or concurrent infections. The β-herpesvirus HCMV (Human Cytomegalovirus) for example infects nearly every second person of an industrialised country. While a lot of people do not notice such an infection at all due to mild symptoms, an infection of an unborn baby by HCMV can lead to life threatening consequences and birth defects of the newborn. Other herpesviruses such as the γ-herpesvirus KSHV (Kaposi Sarcoma Herpesvirus) are known to trigger cancer in humans. KSHV has been classified as class I carcinogen by WHO (World Health Organization) and causes approximately 1% of all cancer cases worldwide.

What’s the current status?

Today, antiviral drugs against herpesviruses exist. These drugs are inhibiting the replication of the viral genome and thus stop virus reproduction. Unfortunately, a lot of the antiviral inhibitors are not effective enough to suppress viral replication fully and permanently and they cannot eliminate the infection. With one exception, all currently available antiviral drugs attack the herpesviruses at the step of viral DNA synthesis by blocking the viral DNA polymerase, the synthesis machinery of viral DNA, which is needed during viral replication. Inhibiting the virus at this stage still allows the expression of certain viral genes and proteins that may play a role during viral pathogenesis.

What are the project goals?

Being able to target other steps in the viral life cycle would significantly improve our ability to devise more efficacious forms of antiviral combination therapy for the affected patients. In particular, it would be desirable to target the immediate-early or early stages of the herpesviral life cycle, as viral genes and proteins expressed during the early stages contribute to the viral pathogenic properties and are required for the ability of these viruses to persist longterm in an infected individual. The key intellectual challenge is to pinpoint points in the viral life cycle and in the complex interaction network of viral and cellular proteins that could be amenable to therapeutic intervention.

How do we get there?

From our 20 year long experience of working on the γ-herpesvirus KSHV, we learned a lot about how the virus manages to establish such a long-lasting infection, to escape the detection by the immune system of the host and yet to be transferred from mother to daughter cell during cell division. In doing so, we concentrated on a particular viral protein, the latency-associated nuclear antigen LANA, which mediates many of these functions and can also reprogram the infected cell for the benefit of the virus (e.g. Rainbow et al., 1997, Platt et al., 1999; Ottinger et al., 2006, 2009; Viejo-Borbolla et al., 2003, 2005; Jäger et al., 2012; Zhang et al., 2016; Mariggio et al., 2017). An important aspect of our work is to understand the structure of LANA (Hellert et a., 2013, 2015) and the nature of tiny ‘territories’ in the nucleus of the infected cell in which the virus resides in a latent form. Over the last 20 years we have also characterized the function of a viral non-structural membrane protein, pK15, which is necessary during the early stages of productive early replication and initiates intracellular signaling pathways required for viral replication. For both LANA and pK15 we have, in collaboration with another RESIST scientist, M. Empting, developed first generation small molecule inhibitors that antagonize the function of LANA or pK15-dependent signal transduction. Within RESIST we want to transfer our gained knowledge and experience from the work on KSHV LANA to other herpesviruses, such as the β-herpesvirus HCMV. We seek to find ‘weak spots’ in the interaction between the virus and the infected cell and to target these spots with novel and more efficient antiviral drugs.

Projectleaders

Project title: Comparative Approach to β and γ-herpesvirus Persistence

Prof. Dr. Thomas F. Schulz

Projekte: D1, D3, RESIST-Kohorte

CV & Contact

Prof. Dr. Thomas Krey

Projekte: B10, D1, D3

CV & Contact

Prof. Dr. Martin Messerle

Projekte: D1, D2

CV & Contact

Prof. Dr. Kay Grünewald

Projekte: D1, D2

CV & Contact

Project D1 Publications

Publications of the Year 2021

3D culture conditions support Kaposi’s sarcoma herpesvirus (KSHV) maintenance and viral spread in endothelial cells. Dubich T, Dittrich A, Bousset K, Geffers R, Büsche G, Köster M, Hauser H, Schulz TF, Wirth D. J Mol Med (Berl). 2021 Mar;99(3):425-438. doi: 10.1007/s00109-020-02020-8. Epub 2021 Jan 23. PMID: 33484281 Free PMC article.

Publications of the Year 2020

Quantitative Proteomics Analysis of Lytic KSHV Infection in Human Endothelial Cells Reveals Targets of Viral Immune Modulation Gabaev I, Williamson JC, Crozier TWM, Schulz TF, Lehner PJ.  Cell Rep 2020;33(2):108249 D1

Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi’s Sarcoma-Associated Herpesvirus ACS Kirsch P, Jakob V, Elgaher WAM, Walt C, Oberhausen K, Schulz TF, Empting M.  Chem Biol 2020;15(2):388-395 D1

Hit-to-lead optimization of a latency-associated nuclear antigen inhibitor against Kaposi’s sarcoma-associated herpesvirus infections Kirsch P, Stein SC, Berwanger A, Rinkes J, Jakob V, Schulz TF, Empting M.  Eur J Med Chem 2020;202:112525 D1

Brd/BET Proteins Influence the Genome-Wide Localization of the Kaposi’s Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus Major Latency Proteins Lotke R, Schneeweiss U, Pietrek M, Günther T, Grundhoff A, Weidner-Glunde M, Schulz TF.  Front Microbiol 2020;11:591778 D1

Whole-Genome Approach to Assessing Human Cytomegalovirus Dynamics in Transplant Patients Undergoing Antiviral Therapy Suarez NM, Blyth E, Li K, Ganzenmueller T, Camiolo S, Avdic S, Withers B, Linnenweber-Held S, Gwinner W, Dhingra A, Heim A, Schulz TF, Gunson R, Gottlieb D, Slobedman B, Davison AJ.  Front Cell Infect Microbiol 2020;10:267 D1

Publications of the Year 2019

Kaposi’s sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression Koch S, Damas M, Freise A, Hage E, Dhingra A, Rückert J, Gallo A, Kremmer E, Tegge W, Brönstrup M, Brune W, Schulz TF. PLoS Pathog 2019;15(5):e1007743 D1

Project D1
Publications