Main research topic
Kaposi Sarcoma-associated Herpesvirus (KSHV), or Human Herpesvirus 8 (HHV8), is the infectious cause of Kaposi’s sarcoma (KS), an endothelial cell – derived tumour. KS occurs frequently in patients living with HIV, mostly in those that do not receive antiretroviral combination therapy, but can also occur in patients whose HIV viral load is well controlled. KS is one of the leading cause of cancer in men in sub-Saharan Africa. In addition, KS can occur in other immunosuppressed individuals, in particular in transplant recipients living in KSHV-endemic countries. In East and Central Africa, endemic KS occurs in HIV-negative persons, ‘classic’ KS, a more indolent form of the disease, is a rare tumour mainly in elderly men in Mediterranean countries. In addition to these variants of KS, KSHV is also the cause of the plasma cell variant of Multicentric Castleman’s disease (MCD) and of primary effusion lymphoma (PEL), two B-cell neoplasms associated with AIDS. KSHV was discovered by Yuan Chang and Pat Moore in 1994 and is one of the seven human cancer viruses recognized by the International Agency for Research against Cancer (IARC), a WHO agency.
Like all herpesviruses, KSHV/HHV8 persists lifelong in infected individuals in a latent non-replicative state, during which no new viral progeny is produced and only a very limited set of viral genes is expressed. This latent state is found in infected B- and endothelial cells and can alternate with bursts of productive (‘lytic’) replication, which allows the production of new viral progeny and the infection of new cells or other individuals.
The longterm aim of our research is to understand how latency functions and how it alters with productive replication. In this context, we are particularly interested in the following topics:
LANA is the main latency protein and is located mainly in the nucleus of a latently infected cells within characteristic nuclear microdomains (‘LANA speckles’). It is used as a histopathology marker to identify KSHV-infected cells in tumour tissue. LANA is indispensable for the replication of the latent episomal viral genome during the S phase of the cell cycle and its distribution to dividing daughter cells. Our work aims at a better understanding of the structure and function of this essential viral protein, as well as of the nature and composition of LANA nuclear microdomains. We try and exploit a better understanding of LANA and its function to develop small molecule inhibitors that interfere with the role of LANA during viral persistence and could provide the basis for a new class of antiviral drugs. This research is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) in the framework of the Collaborative Research Centre 900 (‘Chronic Infections: Microbial Persistene and its control’), the Cluster of Excellence 2155 RESIST (‘Resolving Infection Susceptibility‘) and by the German Center for Infection Research (DZIF).
The KSHV open reading frame (ORF) K15 encodes a non-structural membrane protein, which resembles the latent membrane proteins LMP1 and LMP2A of Epstein-Barr virus (EBV), another oncogenic herpesvirus. Over the last years we could show that this protein, pK15, contributes to the aberrant differentiation and migration of KSHV-infected endothelial cells, as well as the reactivation of KSHV from latency; we could also show that KSHV is widely expressed in KSHV-infected tumour cells in KS tissue. This protein acts by recruiting and activating the phosphorylation of the cellular phospholipase PLCg1 and downstream signaling pathways activated by PLCg1. We try to understand how pK15 promotes the phosphorylation and activation of PLCg1 by cellular tyrosine kinases. Based on a better understanding of the mechanisms involved we attempt to develop small molecule inhibitors that antagonize pK15-dependent signaling pathways and with it KSHV reactivation from latency. This research has been funded by DFG in CRC 566 and by individual DFG project grants and is currently supported by DZIF and the cluster of excellence RESIST.
Type I and III interferons represent effectors of the innate immune system and are known to suppress the replication of many DNA and RNA viruses. We observed recently that KSHV can take advantage of the interferon system to regulate its own latency. It uses vIRF2, one of its four homologues of cellular interferon regulatory factors, to suppress its own productive (‘lytic’) replication and thus promotes the latency state that is typical for this virus. We are trying to understand the molecular mechanisms involved in this ability of KSHV to exploit a cellular defence mechanism for its own purpose.
The currently available therapeutic options to treat KSHV-associated diseases such as Kaposi’s Sarcoma, primary effusion lymphoma and multicentric Castleman’s disease are still very limited. Although inhibitors of herpesviral DNA polymerase used against other herpesviruses, e.g. cidofovir, foscarnet, brivudine, are capable of inhibiting productive KSHV replication in tissue culture, these drugs are ineffective against established KSHV diseases. This likely reflects the fact that the latent state of KSHV, or certain viral proteins expressed in cells that do not undergo full productive replication, are essential for the development of KSHV-associated tumours, and that the inhibition of the lytic replication cycle by existing drugs is therefore ineffective.
With support from the German Center for Infection Research (DZIF) we therefore work on the development of new compounds that target the viral latent phase, or very early steps in the productive (‘lytic’) replication cycle and which might therefore provide the basis for the development of drugs to treat KSHV-associated diseases.
Team Leader and director from institute of virology
- Prof. Dr. med. Thomas F. Schulz
Hannover Medical School, MHH
Institute of Virology, OE5230
Phone: +49 511 532 6736
Departmental Secretary: +49 511 532 6736
Laboratory: +49 511 532 4324
FAX: + 49 511 532 8736
Prof. T.F. Schulz, MD qualified in medicine in 1979 (Mainz University), initially trained in Internal Medicine (1979-81) and then in Medical Microbiology in Mainz (1981-1983) and Innsbruck (1983-1988). Following his ‘Habilitation’ in Innsbruck in 1986, he moved to the Institute of Cancer Research in London as a longterm EMBO Fellow (1988-90) and Clinical Research Scientist (1990-1995), where he worked on the human retroviruses HIV-1, HIV-2 and HTLV-1, and, from 1994 onwards, on KSHV/HHV8. He was appointed as full professor in the Department of Medical Microbiology at the University of Liverpool in 1995, where he worked on the epidemiology and molecular biology of KSHV/HHV8. In 2000 he became Professor of Virology and Head of the Institute of Virology at Hannover Medical School. Dr. Schulz is ‘speaker’ (scientific coordinator) of the DFG-funded Collaborative Research Centre 900 on Chronic Infections and of the Cluster of Excellence 2155 ‘RESIST’ (‘Resolving Infection Susceptibility’). He is also coordinator of the thematic area ‘Infections of the Immunocompromised Host’ of the German Center for Infection Research (DZIF).
Stein, Saskia, Dr., Postdoc
+49 511 532 6493 | Stein.Saskia@MH-Hannover.de
Zischke, Jasmin, Dr. , Postdoc
+49 511 532 19821 | Zischke.Jasmin@MH-Hannover.de
Cramer, Johannes, Postdoc
+49 511 532 4225 | Cramer.Johannes@MH-Hannover.de
Naimo, Eleonora, MSc, PhD Student
+49 511 532 8323 | Naimo.Eleonora@mh-hannover.de
Freise, Anika, Msc, PhD Student
+49 511 532 4324 | Freise.Anika@MH-Hannover.de
Götting, Jasper, Msc, PhD Student
+49 511 532 4313 | Goetting.Jasper@MH-Hannover.de
Tikla, Tanvi, Msc, PhD Student
+49 511 532 8323 | Tikla.Tanvi@MH-Hannover.de
Jandhyala, Sunayana Shyam, Msc, PhD Student
+49 511 532 8323 | Jandhyala.Sunayana@MH-Hannover.de
Azadegan, Azadeh, Msc, PhD Student
+49 511 532 4324 | Azadegan.Azadeh@MH-Hannover.de
Kroglowski, Alessandra, PhD Student
+49 511 532 19821 | Kroglowski.Alessandra@MH-Hannover.de
Waldmann, Ja-Yun, Msc. rer.nat.
+49 511 532 8323 | Waldmann.Ja-Yun@MH-Hannover.de
Steinbrück, Lars, MTA
+49 511 532 4313 | Steinbrueck.Lars@MH-Hannover.de
Rückert, Jessica, BTA
+49 511 532 4324 | Rueckert.Jessica@MH-Hannover.de
Alamirew, Bizunesh, PhD
Alkharsah, Khaled, PhD
Bala, Kiran, PhD
Beauclair, Guillaume, PhD
Bosco, Rafaella, PhD
Brinkmann, Melanie, Dr. rer. nat.
Damas, Modester, PhD
Dedicoat, Martin, PhD
Dhingra, Akshay, PhD
Gellermann, Eva, Dr. rer. nat.
Gramolelli, Silvia, PhD
Gupta, Saumya, PhD
Haas, Darya, PhD
Hävemeier, Anika, Dr. rer. nat.
Hage, Elias, PhD
Hartmann, Silke, Dr. rer. nat.
Jäger, Wiebke, Dr. rer. nat.
Kati, Emrah, Dr. med.
Kati, Semrah, Dr. rer. nat.
Koch, Sandra, Dr. rer. nat.
Lotke, Rishikesh, PhD
Mariggiò, Giuseppe, PhD
Nivia, David, PhD
Ottinger, Matthias, Dr. rer. nat.
Pietrek, Marcel, Dr. rer. nat.
Richter, Ulrike, Dr. rer. nat.
Samarina, Naira, Dr. rer. nat.
Santag, Susan, Dr. rer. nat.
Singh, Vivek, PhD
Soltani, Samira, Dr. med.
Schmidt, Merle, Dr. med.
Wang, Linding, PhD
Weidner-Glunde, Magdalena, PhD
Yakushko, Yuri, PhD
Zhang, Guigen, PhD
Key Original Publications on KSHV/HHV8:
Koch S, Damas M, Freise A, Hage E, Dhingra A, Rückert J, Gallo A, Tegge W, Brönstrup M, Brune W, Schulz TF Kaposi’s sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression. PLoS Pathogens 2019; 15(5):e1007743
Abere B, Samarina N, Gramolelli S, Rückert J, Gerold G, Pich A, Schulz TF Kaposi’s sarcoma-associated Herpesvirus nonstructural membrane protein pK15 recruits the class II phosphatidylinositol 3-kinase PI3K-C2a to activate productive viral replication. J. Virol. 2018; 92:e00544-18. doi.org/10.1128/JVI.00544-18
Abere B, Mamo TM, Hartmann S, Samarina N, Hage E, Rückert J, Hotop SK, Büsche G, Schulz TF The Kaposi’s Sarcoma-associated Herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target. PLoS Pathog. 2017; 3(9): e1006639. doi: 10.1371/journal.ppat.1006639
Mariggiò G, Koch S, Zhang G, Weidner-Glunde M, Rückert J, Kati S, Santag S, Schulz TF Kaposi Sarcoma Herpesvirus Latent Nuclear Antigen (LANA) recruits components of the MRN (Mre11-Rad50-Nbs1) complex to modulate an innate immune signaling pathway and viral latency. PLoS Pathog. 2017; 13:e1006335. doi: 10.1371/journal.ppat.1006335.
Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M, Buch A, Pich A, Brinkmann MB, Schulz TF. Cytoplasmic isoforms of Kaposi Sarcoma Herpesvirus LANA recruit and antagonize the innate immune sensor cGAS. Proc Natl Acad Sci U S A. 2016; 113(8):E1034-43. doi: 10.1073/pnas.1516812113.
Gramolelli S, Weidner-Glunde M, Abere B, Viejo-Borbolla A, Bala K, Rückert J, Kremmer E, Schulz TF. Inhibiting the recruitment of PLCg1 to Kaposi’s Sarcoma Herpesvirus K15 protein reduces the invasiveness and angiogenesis of infected endothelial cells. PLoS Pathog. 2015; 11(8):e1005105. doi: 10.1371/journal.ppat.1005105
Hellert J, Weidner-Glunde M, Krausze J, Lünsdorf H, Ritter C, Schulz TF*, Lührs T*. The 3D-structure of Kaposi’s sarcoma herpesvirus LANA c-terminal domain bound to DNA. Proc Natl Acad Sci U S A. 2015; 112: 6694-9. *joint senior author
Hävemeier A, Gramolelli S, Pietrek M, Jochmann R, Stürzl M, Schulz TF. Activation of NFkB by the Kaposi Sarcoma Hepresvirus K15 protein involves recruitment of the NFkB-inducing kinase, IkB kinases, and phosphorylation of p65. J Virol. 2014; 88:13161-72. doi: 10.1128/JVI.01766-14.
Hellert J, Weidner-Glunde M, Krausze J, Richter U, Adler H, Fedorov R, Pietrek M, Rückert J, Ritter C, Schulz TF*, Lührs T*. A structural basis for BRD2/4-mediated host chromatin interaction and oligomer assembly of Kaposi Sarcoma Herpesvirus and murine gammaherpesvirus LANA proteins. PLoS Pathogens 2013; 9(10):e1003640. doi: 10.1371 *joint senior authors
Haas DA, Bala K, Büsche G, Weidner-Glunde M, Santag S, Kati S, Gramolelli S, Damas M, Dittrich-Breiholz O, Kracht M, Rückert J, Varga Z, Keri G, Schulz TF The inflammatory kinase MAP4K4 promotes reactivation promotes reactivation of Kaposi’s Sarcoma Herpesvirus and enhances the invasiveness of infected endothelial cells. PLoS Pathogens 2013; 9(11):e1003737. doi: 10.1371/ journal.ppat.1003737.
Gupta SS, Maetzig T, Maertens GN, Sharif A, Rothe M, Weidner-Glunde M, Galla M, Schambach A, Cherepanov P, Schulz TF Bromo- and ET domain (BET) chromatin regulators serve as co-factors for murine leukemia virus integration. J. Virol. 2013; 87:12721-36. doi: 10.1128/JVI.01942-13
Santag S, Jäger W, Karsten C, Kati S, Pietrek M, Steinemann D, Sarek G, Ojala P, Schulz TF Recruitment of the tumour suppressor protein p73 by Kaposi Sarcoma Herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells. Oncogene, 2012; doi: 10.1038/onc.2012.385.
Bala K, Bosco R, Gramolelli S, Haas DA, Kati S, Pietrek M, Hävemeier A, Yakushko Y, Singh VV, Dittrich-Breiholz O, Kracht M, Schulz TF Kaposi´s Sarcoma Herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCg1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathogens 2012; 8:e1002927. doi: 10.1371
Jäger W, Santag S, Weidner-Glunde M, Gellermann E, Pietrek M, Viejo-Borbolla A, Schulz TF The ubiquitin-specific protease USP7 modulates the replication of KSHV latent episomal DNA. J. Virol., 2012; 86: 6745-57
Alkharsah KR, Schulz TF. A role for the internal repeat of the Kaposi's sarcoma-associated herpesvirus latent nuclear antigen in the persistence of an episomal viral genome. J. Virol. 2012; 86:1883-7.
Alkharsah KR, Singh VV, Bosco R, Santag S, Grundhoff A, Konrad A, Sturzl M, Wirth D, Dittrich-Breiholz O, Kracht M, Schulz TF. Deletion of Kaposi's sarcoma-associated herpesvirus FLICE inhibitory protein, vFLIP, from the viral genome compromises the activation of STAT1-responsive cellular genes and spindle cell formation in endothelial cells. J. Virol. 2011; 85:10375-88.
Pietrek M, Brinkmann MM, Glowacka I, Enlund A, Havemeier A, Dittrich-Breiholz O, Kracht M, Lewitzky M, Saksela K, Feller SM, Schulz TF. Role of the Kaposi's sarcoma-associated herpesvirus K15 SH3 binding site in inflammatory signaling and B-cell activation. J. Virol. 2011; 84:8231-40.
Ottinger M, Pliquet D, Christalla T, Frank R, Stewart JP, Schulz TF. The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins affects the activation of cell cycle promoters. J. Virol. 2009; 83:4423-4434
Brinkmann M, Pietrek M, Dittrich-Breiholz O, Kracht M, Schulz TF Modulation of host gene expression by the K15 protein of Kaposi’s sarcoma-associated herpesvirus J. Virol. 2007; 81: 42-58.
Ottinger M, Christalla T, Nathan K, Brinkmann M, Viejo-Borbolla A, Schulz TF The Kaposi’s Sarcoma-Associated Herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3- induced G1 cell cycle arrest J. Virol. 2006; 80: 10772-86
Viejo-Borbolla A, Ottinger M, Bruning E, Burger A, Konig R, Kati E, Sheldon JA, Schulz TF. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's Sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J Virol. 2005; 79:13618-29.
Dedicoat M, Newton R, Alkharsah K.R, Sheldon J, Szabados I, Ndlovu B, Page T, Casabonne D, Gilks CF, Cassol SA, Whitby D, Schulz TF Mother to child transmission of human herpesvirus 8 in South Africa. J. Inf. Dis. 2004; 190:1068-75
Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein. J Virol. 2003; 77: 9346-58
Viejo-Borbolla A, Kati E, Sheldon J, Nathan K, Mattsson K, Szekely L, Schulz TF A domain in the C-terminal region of latency - associated nuclear antigen (LANA-1) of KSHV affects transcriptional activation and binding to nuclear heterochromatin. J Virol. 2003; 77: 7093-100.
Barozzi P, Luppi M, Facchetti F, Mecucci C, Alu M, Sarid R, Rasini V, Ravazzini L, Rossi E, Festa S, Crescenzi B, Wolf DG, Schulz TF, Torelli G. Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors. Nature Medicine 2003; 9: 554-61.
Luppi M, Barozzi P, Schulz TF, Setti G, Staskus K, Trovato R, Narni F, Donelli A, Maiorana A, Marasca R, Sandrini S, Torelli G, Sheldon J. (2000) Bone Marrow failure associated with Human Herpesvirus 8 infection after transplantation N Engl J Med 2000; 343: 1378-1385
Greensill J, Sheldon J, Renwick NM, Beer B, Norley S, Goudsmit J, Schulz TF Two distinct 2 herpesviruses in African Green monkeys: a second 2 herpesvirus lineage among Old World primates? J. Virol. 2000; 74: 1572 - 1577.
Greensill J, Sheldon JA, Murthy KK, Bessonette JS, Beer BE, Schulz TF A chimpanzee rhadinovirus closely related to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8: increased detection after HIV-1 infection in the absence of disease. AIDS 2000; 14: F129 - 135
Glenn, M., Rainbow, L., Aurade, F., Davsion, A., Schulz, T.F. Identification of a multiply spliced gene of KSHV/HHV8 with similarities to the latent membrane proteins of EBV. J.Virol. 1999; 73: 6953 – 6963
Platt GM, Simpson GR, Mittnacht S, Schulz TF Latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts with RING3, a homolog of the Drosophila female sterile homeotic (fsh) gene."J. Virol. 1999; 73: 9789 - 9795.
Farge D, Lebbé C, Marjanovic Z, Tuppin P, Mouquet C, Peraldi MN, Lang P, Hiesse C, Antoine C, Legendre C, Bedrossian J, Gagnadoux MF, Loirat C, Pellet C, Sheldon J, Golmard JL, Agbalika F, Schulz TF. Human herpesvirus 8 (HHV 8) and other risk factors for Kaposi’s sarcoma in kidney transplant recipients. Transplantation 1999; 67: 1236 – 1242
Cook PM, Whitby D, Calabro ML, Luppi M, Kakoola DN, Hjalgrim H, Ariyoshi K, Ensoli B, Davison AJ, Schulz TF, and the International Collaborative Group. Variability and evolution of Kaposi's sarcoma-associated herpesvirus in Europe and Africa. AIDS 1999; 13: 1165 - 1176
Melbye M, Cook PM, Hjalgrim H, Begtrup K, Simpson GR, Biggar RJ, Ebbesen P, Schulz TF. "Risk factors for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) seropositivity in a cohort of homosexual men, 1981 - 1996." Int. J. Cancer, 1998; 77: 543-548
Mayama S, Cuevas L, Sheldon J, Smith D, Okong P, Silvel B, Schulz TF. "Prevalence of Kaposi’s sarcoma associated herpesvirus (Human herpesvirus 8) in a young Ugandan population." Int. J. Cancer, 1998; 77: 817-820
Renwick N, Halaby T, Weverling GJ, Simpson GR, Coutinho RA, Lange JMA, Schulz TF, Goudsmit J Seroconversion for Kaposi’s sarcoma-associated herpesvirus is highly predictive of KS development in HIV-1 infected individuals. AIDS 1998; 12: 2481 - 2488
Rainbow, L., Platt, G.M., Simpson, G.R., Sarid, R., Gao, S.-J., Stoiber, H., Herringston, C.S., Moore, P.S., Schulz, T.F. The 222-234 kd nuclear protein (LNA) of Kaposi's sarcoma - associated herpesvirus (KSHV/HHV 8) is encoded by orf73 and a component of the latency-associated nuclear antigen (LANA). J.Virol. 1997; 71: 5915-5921
Simpson, G.R., Schulz,T.F.*, Whitby,D., Cook,P.M., Boshoff, C., Rainbow, L., Howard, M., Gao, S.-J., Bohenzky, R.A., Simmonds, P., Lee, C., de Ruiter, A., Hatzakis, A., Tedder, R.S., Weller, I.V.D., Weiss, R.A., Moore, P.S. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 1996; 348:1133 – 1138 *corresponding author
Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, Hatzioannou T, Suggett FEA, Aldam DM, Denton AS, Miller RF, Weller IVD, Weiss RA, Tedder RS, Schulz TF. Detection of Kaposi's sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet 1995; 346:799-802.
Boshoff C, Schulz TF, Kennedy MM, Graham AK, Fisher C, Thomas A, McGee J, Weiss RA, O'Leary JJ Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nature Medicine 1995; 1: 1274-1278