Experimentelle Virologie

Forschungsschwerpunkte

• Persistierende virale Infektionen
• Angeborene Immunität gegen Retroviren
• Grundlagen zellulärer und molekularer Immunabwehrmechanismen
• Immunregulation bei Retrovirus Infektionen
• Immuntherapie gegen retrovirale Infektionen und Virus-induzierte Tumoren
• Entwicklung von Impfstoffen gegen Retroviren
• Antivirale Aktivität von Interferonen

Retrovirale Infektionen

Trotz weltweit intensiver Forschung ist es bisher nicht gelungen, Impfstoffe gegen humanpathogene Retroviren, wie HTLV und HIV, zu entwickeln. Die klassischen Methoden der Impfstoffentwicklung gegen Viren sind bei Retroviren bisher weitestgehend fehlgeschlagen. Daher müssen neue Ansätze ermittelt werden, um erfolgreich Impfstoffe gegen Retroviren herstellen zu können. Wir verwenden ein Mausmodell, die Infektion von Mäusen mit dem „Friend Murine Leukemia Virus“ (FV), um grundlegende immunologische Mechanismen des Impfschutzes gegen Retroviren aufzuklären. Darüber hinaus untersuchen wir, welche Mediatoren des Immunsystems für die Kontrolle einer chronischen Infektion mit Retroviren wichtig sind. Die Erkenntnisse aus diesen Untersuchungen werden verwendet, um neue Immuntherapien und Impfstoffe gegen Retroviren zu entwickeln.

Arbeitsgruppe

Leiter

Prof. Dr. rer. nat. Ulf Dittmer
Tel: +49 (0)201 723 3550
E-Mail: ulf.dittmer@uni-due.de

Ausgewählte Publikationen

Treatment of Chronic Hepatitis B Virus Infection Using Small Molecule Modulators of Nucleocapsid Assembly: Recent Advances and Perspectives. Yang L, Liu F, Tong X, Hoffmann D, Zuo J, Lu M. ACS Infectious Diseases 2019 (5), 713-724.

PASylated interferon α efficiently suppresses hepatitis B virus and induces anti-HBs seroconversion in HBV-transgenic mice. Xia Y, Schlapschy M, Morath V, Roeder N, Vogt EI, Stadler D, Cheng X, Dittmer U, Sutter K, Heikenwalder M, Skerra A, Protzer U. Antiviral Research 2019 (161), 134-143.

Plasmacytoid dendritic cells respond to Epstein-Barr virus infection with a distinct type I interferon subtype profile. Gujer C, Murer A, Müller A, Vanoaica D, Sutter K, Jacque E, Fournier N, Kalchschmidt J, Zbinden A, Capaul R, Dzionek A, Mondon P, Dittmer U, Münz C. Blood Advances 2019 (3), 1129-1144.

Chronic retroviral infection of mice promotes tumor development, but CD137 agonist therapy restores effective tumor immune surveillance. Malyshkina A, Littwitz-Salomon E, Sutter K, Ross JA, Paschen A, Windmann S, Schimmer S, Dittmer U. Cancer Immunology, Immunotherapy 2019 (68), 479-488.

IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation. Hotter D, Bosso M, Jønsson KL, Krapp C, Stürzel CM, Das A, Littwitz-Salomon E, Berkhout B, Russ A, Wittmann S, Gramberg T, Zheng Y, Martins LJ, Planelles V, Jakobsen MR, Hahn BH, Dittmer U, Sauter D, Kirchhoff F. Cell Host & Microbe 2019 (25), 858-872.e813.

Activation of the TLR signaling pathway in CD8+ T cells counteracts liver endothelial cell-induced T cell tolerance. Zhang E, Yan H, Li Q, Dittmer U, Yan H, Lu M. Cellular & Molecular Immunology 2019 (16), 774-776.

Guanylate-Binding Proteins 2 and 5 Exert Broad Antiviral Activity by Inhibiting Furin-Mediated Processing of Viral Envelope Proteins. Braun E, Hotter D, Koepke L, Zech F, Groß R, Sparrer KMJ, Müller JA, Pfaller CK, Heusinger E, Wombacher R, Sutter K, Dittmer U, Winkler M, Simmons G, Jakobsen MR, Conzelmann K-K, Pöhlmann S, Münch J, Fackler OT, Kirchhoff F, Sauter D. Cell Reports 2019 (27), 2092-2104.e2010.

HLA-E Polymorphism Determines Susceptibility to BK Virus Nephropathy after Living-Donor Kidney Transplant. Rohn H, Michita RT, Schramm S, Dolff S, Gäckler A, Korth J, Heinemann FM, Wilde B, Trilling M, Horn PA, Kribben A, Witzke O, Rebmann V. Cells 2019 (8), 847.

Pattern Recognition Receptors and Liver Failure. Wu J, Han M, Li J, Yang X, Zhen X, Schlaak JF, Yang D, Lu M. Critical Reviews in Immunology 2019 (39), 289-311.

Hepatitis B virus mutation pattern rtL180M+A181C+M204V may contribute to entecavir resistance in clinical practice. Liu Y, Zhou Y, Li X, Niu M, Chen R, Shao J, Si L, Luo D, Lin Y, Li L, Zhang K, Xiao X, Xu Z, Liu M, Lu M, Zoulim F, Xu D. Emerging Microbes & Infections 2019 (8), 354-365.

Automated nucleic acid isolation methods for HDV viral load quantification can lead to viral load underestimation. Bremer B, Anastasiou OE, Ciesek S, Wedemeyer H. Antiviral Therapy 2018 (24), 117-123.

MDSCs in infectious diseases: regulation, roles, and readjustment. Dorhoi A, Glaría E, Garcia-Tellez T, Nieuwenhuizen NE, Zelinskyy G, Favier B, Singh A, Ehrchen J, Gujer C, Münz C, Saraiva M, Sohrabi Y, Sousa AE, Delputte P, Müller-Trutwin M, Valledor AF. Cancer Immunology, Immunotherapy 2018 (68), 673-685.

Rapid Rebound of a Preexisting CXCR4-tropic Human Immunodeficiency Virus Variant After Allogeneic Transplantation With CCR5 Δ32 Homozygous Stem Cells. Verheyen J, Thielen A, Lübke N, Dirks M, Widera M, Dittmer U, Kordelas L, Däumer M, de Jong DCM, Wensing AMJ, Kaiser R, Nijhuis M, Esser S. Clinical Infectious Diseases 2018 (68), 684-687.

Antiviral potential of human IFN-α subtypes against influenza A H3N2 infection in human lung explants reveals subtype-specific activities. Matos ADR, Wunderlich K, Schloer S, Schughart K, Geffers R, Seders M, Witt M, Christersson A, Wiewrodt R, Wiebe K, Barth P, Hocke A, Hippenstiel S, Hönzke K, Dittmer U, Sutter K, Rescher U, Rodionycheva S, Matera N, Ludwig S, Brunotte L. Emerg Microbes Infect. 2019;8(1):1763-1776.

Concurrent administration of IFNα14 and cART in TKO-BLT mice enhances suppression of HIV-1 viremia but does not eliminate the latent reservoir. Sutter K, Lavender KJ, Messer RJ, Widera M, Williams K, Race B, Hasenkrug KJ, Dittmer U. Sci Rep. 2019 Dec 2;9(1):18089.

MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance. Yang S, Wang L, Pan W, Bayer W, Thoens C, Heim K, Dittmer U, Timm J, Wang Q, Yu Q, Luo J, Liu Y, Hofmann M, Thimme R, Zhang X, Chen H, Wang H, Feng X, Yang X, Lu Y, Lu M, Yang D, Liu J. J Hepatol. 2019 Oct;71(4):685-698.

Diverse Immunomodulatory Effects of Individual IFNα Subtypes on Virus-Specific CD8+ T Cell Responses. Dickow J, Francois S, Kaiserling RL, Malyshkina A, Drexler I, Westendorf AM, Lang KS, Santiago ML, Dittmer U, Sutter K. Front Immunol. 2019 Sep 24;10:2255.

IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation. Hotter D, Bosso M, Jønsson KL, Krapp C, Stürzel CM, Das A, Littwitz-Salomon E, Berkhout B, Russ A, Wittmann S, Gramberg T, Zheng Y, Martins LJ, Planelles V, Jakobsen MR, Hahn BH, Dittmer U, Sauter D, Kirchhoff F. Cell Host Microbe. 2019 Jun 12;25(6):858-872.e13.

Chronic retroviral infection of mice promotes tumor development, but CD137 agonist therapy restores effective tumor immune surveillance. Malyshkina A, Littwitz-Salomon E, Sutter K, Ross JA, Paschen A, Windmann S, Schimmer S, Dittmer U. Cancer Immunol Immunother. 2019 Mar;68(3):479-488.

Infection of B Cell Follicle-Resident Cells by Friend Retrovirus Occurs during Acute Infection and Is Maintained during Viral Persistence. Windmann S, Otto L, Hrycak CP, Malyshkina A, Bongard N, David P, Gunzer M, Dittmer U, Bayer W. mBio. 2019 Feb 19;10(1). pii: e00004-19.

Rapid Rebound of a Preexisting CXCR4-tropic Human Immunodeficiency Virus Variant After Allogeneic Transplantation With CCR5 Δ32 Homozygous Stem Cells. Verheyen J, Thielen A, Lübke N, Dirks M, Widera M, Dittmer U, Kordelas L, Däumer M, de Jong DCM, Wensing AMJ, Kaiser R, Nijhuis M, Esser S. Clin Infect Dis. 2019 Feb 1;68(4):684-687.

Friend retrovirus infection induces the development of memory-like natural killer cells. Littwitz-Salomon E, Nguyen T, Schimmer S, Dittmer U. Retrovirology. 2018 Oct 6;15(1):68.

Imaging of cytotoxic antiviral immunity while considering the 3R principle of animal research. Otto L, Zelinskyy G, Schuster M, Dittmer U, Gunzer M. J Mol Med (Berl). 2018 Apr;96(3-4):349-360.

Hepatitis B virus sensitivity to interferon-α in hepatocytes is more associated with cellular interferon response than with viral genotype. Shen F, Li Y, Wang Y, Sozzi V, Revill PA, Liu J, Gao L, Yang G, Lu M, Sutter K, Dittmer U, Chen J, Yuan Z. Hepatology. 2018 Apr;67(4):1237-1252.

Fas Ligand-mediated cytotoxicity of CD4+ T cells during chronic retrovirus infection. Malyshkina A, Littwitz-Salomon E, Sutter K, Zelinskyy G, Windmann S, Schimmer S, Paschen A, Streeck H, Hasenkrug KJ, Dittmer U. Sci Rep. 2017 Aug 10;7(1):7785.

Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo. Lavender KJ, Gibbert K, Peterson KE, Van Dis E, Francois S, Woods T, Messer RJ, Gawanbacht A, Müller JA, Münch J, Phillips K, Race B, Harper MS, Guo K, Lee EJ, Trilling M, Hengel H, Piehler J, Verheyen J, Wilson CC, Santiago ML, Hasenkrug KJ, Dittmer U. J Virol. 2016 Jun 10;90(13):6001-6013.

Schultz BT, Teigler JE, Pissani F, Oster AF, Kranias G, Alter G, Marovich M, Eller MA, Dittmer U, Robb ML, Kim JH, Michael NL, Bolton D, Streeck H. Circulating HIV-Specific Interleukin-21(+)CD4(+) T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions. Immunity. 2016 Jan 19;44(1):167-78.

Akhmetzyanova I, Zelinskyy G, Littwitz-Salomon E, Malyshkina A, Dietze KK, Streeck H, Brandau S, Dittmer U. CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity. J Immunol. 2016 Jan 1;196(1):484-92.

Harper MS, Guo K, Gibbert K, Lee EJ, Dillon SM, Barrett BS, McCarter MD, Hasenkrug KJ, Dittmer U, Wilson CC, Santiago ML. Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms. PLoS Pathog. 2015 Nov 3;11(11):e1005254.

Akhmetzyanova I, Drabczyk M, Neff CP, Gibbert K, Dietze KK, Werner T, Liu J, Chen L, Lang KS, Palmer BE, Dittmer U, Zelinskyy G. PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape from CD8+ T Cell Killing. PLoS Pathog. 2015 Oct 20;11(10):e1005224.

Littwitz-Salomon E, Akhmetzyanova I, Vallet C, Francois S, Dittmer U, Gibbert K. Activated regulatory T cells suppress effector NK cell responses by an IL-2-mediated mechanism during an acute retroviral infection. Retrovirology. 2015; 12: 66.

Gibbert K, Francois S, Sigmund AM, Harper MS, Barrett BS, Kirchning CJ, Lu M, Santiago ML, Dittmer U. Friend retrovirus drives cytotoxic effectors through Toll-like receptor 3. Retrovirology. 2014 Dec 24;11:126.

Joedicke JJ, Myers L, Carmody AB, Messer RJ, Wajant H, Lang KS, Lang PA, Mak TW, Hasenkrug KJ, Dittmer U. Activated CD8+ T Cells Induce Expansion of Vβ5+ Regulatory T Cells via TNFR2 Signaling. J Immunol. 2014 Sep 15;193(6):2952-60.

Kordelas L, Verheyen J, Beelen DW, Horn PA, Heinold A, Kaiser R, Trenschel R, Schadendorf D, Dittmer U, Esser S; Essen HIV AlloSCT Group. Shift of HIV tropism in stem-cell transplantation with CCR5 Delta32 mutation. N Engl J Med. 2014 Aug 28;371(9):880-2

Dietze KK, Zelinskyy G, Liu J, Kretzmer F, Schimmer S, Dittmer U. Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads. PLoS Pathog. 2013;9(12):e1003798.

Lavender KJ, Pang WW, Messer RJ, Duley AK, Race B, Phillips K, Scott D, Peterson KE, Chan CK, Dittmer U, Dudek T, Allen TM, Weissman IL, Hasenkrug KJ. BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood. 2013 Dec 12;122(25):4013-20.

Littwitz E, Francois S, Dittmer U, Gibbert K. Distinct roles of NK cells in viral immunity during different phases of acute Friend retrovirus infection. Retrovirology. 2013 Nov 1;10:127.

Akhmetzyanova I, Zelinskyy G, Schimmer S, Brandau S, Altenhoff P, Sparwasser T, Dittmer U. Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells. Cancer Immunol Immunother. 2013 Feb;62(2):257-71.

Gibbert K, Joedicke JJ, Meryk A, Trilling M, Francois S, Duppach J, Kraft A, Lang KS, Dittmer U. Interferon-alpha subtype 11 activates NK cells and enables control of retroviral infection. PLoS Pathog. 2012;8(8):e1002868.

Zelinskyy G, Myers L, Dietze KK, Gibbert K, Roggendorf M, Liu J, Lu M, Kraft AR, Teichgräber V, Hasenkrug KJ, Dittmer U. Virus-specific CD8+ T cells upregulate programmed death-1 expression during acute friend retrovirus infection but are highly cytotoxic and control virus replication. J Immunol. 2011 Oct 1;187(7):3730-7.

Dietze KK, Zelinskyy G, Gibbert K, Schimmer S, Francois S, Myers L, Sparwasser T, Hasenkrug KJ, Dittmer U. Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2420-5.

Zelinskyy G, Dietze KK, Hüsecken YP, Schimmer S, Nair S, Werner T, Gibbert K, Kershaw K, Gruber AD, Sparwasser T & Dittmer U. The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response. Blood 2009; 114: 3199-3207.

Balkow S, Krux F, Loser K, Becker JU, Grabbe S & Dittmer U. Friend retrovirus infection of myeloid dendritic cells impairs maturation, prolongs contact to naïve T-cells, and favors expansion of regulatory T-cells. Blood 2007; 110: 3949-3958.

Dittmer U, He H, Messer RJ, Schimmer S, Olbrich ARM, Ohlen C, Greenberg PD, Stromnes IM, Iwashiro M, Sakaguchi S, Evans LH, Peterson KE, Yang G & Hasenkrug KJ. Functional impairment of CD8+ T cells by regulatory T cells during persistent retroviral infection. Immunity 2004; 20: 293-303.

Dittmer U, Brooks DM & Hasenkrug KJ. Requirements for multiple lymphocyte subsets in protection by a live-attenuated vaccine against retroviral infection. Nature Medicine 1999; 5:189-193.

Reviews

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity. Dittmer U, Sutter K, Kassiotis G, Zelinskyy G, Bánki Z, Stoiber H, Santiago ML, Hasenkrug KJ. FEMS Microbiol Rev. 2019 Sep 1;43(5):435-456. doi: 10.

Interferon α subtypes in HIV infection. Sutter K, Dickow J, Dittmer U. Cytokine Growth Factor Rev. 2018 Apr;40:13-18.

Regulatory T cells in retroviral infections. Hasenkrug KJ, Chougnet CA, Dittmer U. PLoS Pathog. 2018 Feb 15;14(2):e1006776.

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells. Littwitz-Salomon E, Dittmer U, Sutter K. Retrovirology. 2016 Nov 8;13(1):77.

Gibbert K, Schlaak JF, Yang D, Dittmer U. IFN-α subtypes: distinct biological activities in anti-viral therapy. Br J Pharmacol. 2013 Mar;168(5):1048-58.

Nair S, Bayer W, Ploquin MJ, Kassiotis G, Hasenkrug KJ, Dittmer U.
Distinct roles of CD4+ T cell subpopulations in retroviral immunity: lessons from the Friend virus mouse model. Retrovirology. 2011 Sep 26;8:76.

Li S, Gowans EJ, Chougnet C, Plebanski M & Dittmer U. Natural regulatory T cells and persistent viral infection. Journal of Virology 2008; 82: 21-30.

Hasenkrug J K & Dittmer U. Immune control and prevention of chronic Friend retrovirus infection. Frontiers in Bioscience 2007; 12: 1544-1551.

Schneider-Schaulies S & Dittmer U. Silencing T-cells or T-cell silencing: concepts in virus-induced immunosuppression. Journal of General Virology 2006; 87: 1423-1438.

Dittmer U & Olbrich A R M. Therapeutic treatment of infectious diseases with immunostimulatory oligonucleotides containing CpG motifs. Current Opinion in Microbiology 2003; 6: 472-477.

Hasenkrug KJ & Dittmer U. The role of CD4 and CD8 T-cells in the recovery and protection from retroviral infection: Lessons from the Friend virus model. Virology 2000; 272: 244-249.