Virologie


Arbeitsgruppe PD Dr. med. Maximilian Muenchhoff

Unsere Forschungsarbeit widmet sich dem Verständnis der Wirt-Virus-Interaktionen der beiden pandemischen Erreger HIV-1 und SARS-CoV-2. Aufbauend auf unserer Plattform für die genomische Überwachung von SARS-CoV-2 untersuchen wir die Evolution des Erregers durch Anpassung an das menschliche Immunsystem. Wir charakterisieren Immun-Escape-Mutationen, die unter Antikörper- und T-Zell-Antworten in neu entstehenden Varianten und in Patienten mit längerer Infektion selektiert werden. Mit einem breiten Interesse an der Immunpathogenese von Virusinfektionen wollen wir immunologische Signaturen entschlüsseln, die mit unterschiedlichen Krankheitsphänotypen in klinischen Kohorten von SARS-CoV-2- und HIV-1-Infizierten verbunden sind. Am Nationalen Referenzzentrum für Retroviren entwickeln wir modernste Methoden zur Quantifizierung und Charakterisierung der HIV-Persistenz in Patientenproben und primären Zellmodellen.

Zur Arbeitsgruppe

Leitung

PD Dr. med. Maximilian Muenchhoff

Maximilian Muenchhoff, MD, works as scientist and medical doctor at the Max von Pettenkofer Institute of Ludwig-Maximilians-Universität (LMU) in Munich, Germany. He grew up in Munich and attended Medical School in Germany, Spain and Australia. During his clinical training he did rotations amongst others in infectious diseases at the LMU Hospital, Munich, and at the Red Cross Childrens Hospital, Cape Town, South Africa. He completed his M.D. thesis at the Technical University Munich (TUM) in collaboration with the University of New South Wales, Sydney, Australia. In 2012 he joined the group of Phillip Goulder at the University of Oxford and spent postdoctoral periods at the HIV Pathogenesis Programme in Durban, South Africa, and the Ragon Institute in Boston, USA. In 2016 he joined the Max von Pettenkofer Institute to complete his specialization in microbiology, virology and epidemiology, and to establish his own research group. In 2022, he received his “Habilitation” in Experimental Virology.

© Michael Till

AG-Mitglieder

Aktuelle Gruppenmitglieder

Maximilian Muenchhoff, MD, principal investigator
E-Mail: muenchhoff@mvp.lmu.de
Phone: +49 89 2180 76851

Anna Fuchs, Master student
E-Mail: Anna.Fuchs@mvp.lmu.de
Phone: +49 89 2180 76850

Linda Jocham, technician
E-Mail: jocham@mvp.lmu.de
Phone: +49 89 2180 76850

Xiaoling Liang, PhD, postdoctoral fellow
E-Mail: liang@mvp.lmu.de
Phone: +49 89 2180 76854

Tiziana Neff, Bachelor student
E-Mail: Neff@mvp.lmu.de
Phone: +49 89 2180 76850

Theresa Vallée
E-Mail: vallee@mvp.lmu.de
Phone: +49 89 2180 76850

Ehemalige Gruppenmitglieder

Özge Limoncu, Master student
Arthur Brommer
Levent Kombak
Corazón Kordas, Master student

@ Münchhoff

Forschung

HIV persistence in viral reservoirs

Despite major efforts current antiretroviral therapy is not curative. The major obstacle to an HIV cure is persistence of HIV in pools of latently and persistently infected cells. Potential therapeutic interventions aiming at an HIV cure depend on precise methods to quantify and study these viral reservoirs. Within the German Center for Infectious Diseases (DZIF) we are establishing a platform to characterize the HIV reservoir using a portfolio of different methods such as digital droplet PCR and optimized viral outgrowth assays. These assays are made available to other scientist and are used in our own studies of HIV infection in primary cell models.

Immunopathogenesis of viral infections

The pathogenesis of viral infections is determined by highly variable degrees of inflammation and adaptive immunity resulting in a diverse spectrum of disease phenotypes. We are studying interactions of HIV and SARS-CoV-2 with the human immune system to delineate signatures that are associated with disease severity.
Together with our clinical colleagues (Johannes Hellmuth and Clemens Scherer) we established the COVID-19 Registerstudie des Klinikums der Universität München (CORKUM) which has recruited more than 1.000 COVID-19 patients so far (https://forschungsportal.med.uni-muenchen.de/corkum/). An extensive collection of diverse biospecimen from this well characterised cohort allows us to integrate molecular data (proteomics, transcriptomics, genomics) with deep clinical data to decipher differential disease trajectories. We are particularly interested in humoral and cellular immune responses in specific patient populations including immunocompromised hosts.

SARS-CoV-2 evolution and immune evasion

Since its recent emergence SARS-CoV-2 is constantly evolving in adaptation to the human host. The development of SARS-CoV-2 variants-of-concern (VoCs) with substantially increased transmissibility and pathogenicity poses a major challenge for the control of the pandemic. Ongoing viral diversification reduces immunity elicited by currently available vaccines or prior infection.

Selection of antibody and CD8 T-cell driven immune escape mutations in a SARS-CoV-2 infected immunocompromised host. In a patient who suffered persistent SARS-CoV-2 infection for 155 days until her death we observed the sequential emergence of immune escape mutations evading antibody and T-cell responses illustrating the plasticity of SARS-CoV-2 to evade adaptive immunity (https://www.nature.com/articles/s41467-022-32772-5).

In collaboration with our colleagues from the laboratory of Helmut Blum at the Gene Center, LMU Munich, we established a high-throughput pipeline for SARS-CoV-2 whole genome sequencing. Building on our previous work on the phylogenetic characterization of transmission chains and local outbreaks, we established a platform for genomic surveillance of SARS-CoV-2 teaming up with all other virological departments in Bavaria (https://www.bay-voc.lmu.de/). This network allows us to monitor in real time SARS-CoV-2 spread and the emergence/introduction of new variants on the population level. Beyond this, we are particularly interested in intra-host evolution of SARS-CoV-2 in adaption to selection pressure mediated by the adaptive immune system in patients with prolonged infection.

We aim to characterize immune escape mutations that are selected under antibody and T-cell selection. Patient isolates are tested for evasion of neutralising antibody responses and for potential T-cell escape mutations. Epitope-specific T-cell responses are characterized in depth by flowcytometry for phenotypic and functional properties. Using high-resolution sequencing of the T-cell receptor (TCR) beta chains we aim to identify antigen-specific common clonotypes and shared TCRs. Finally, we investigate if confirmed escape mutations arise independently in multiple globally circulating lineages demonstrating convergent evolution in adaptation to the human immune system.

Publikationen

Top 10 Publikationen

Khatamzas E, Antwerpen M H, Rehn A, Graf A, Hellmuth J C, Hollaus A, Mohr A W, Gaitzsch E, Weiglein T, Georgi E, Scherer C, Stecher S S, Gruetzner S, Blum H, Krebs S, Reischer A, Leutbecher A, Subklewe M, Dick A, Zange S, Girl P, Muller K, Weigert O, Hopfner K P, Stemmler H J, von Bergwelt-Baildon M, Keppler O T, Wolfel R, Muenchhoff M*, Moosmann A*. Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection. Nature Communications 13:5586 (2022). https://doi.org/10.1038/s41467-022-32772-5
Muenchhoff M, Graf A, Krebs S, Quartucci C, Hasmann S, Hellmuth J C, Scherer C, Osterman A, Boehm S, Mandel C, Becker-Pennrich A S, Zoller M, Stubbe H C, Munker S, Munker D, Milger K, Gapp M, Schneider S, Ruhle A, Jocham L, Nicolai L, Pekayvaz K, Weinberger T, Mairhofer H, Khatamzas E, Hofmann K, Spaeth P M, Bender S, Kaab S, Zwissler B, Mayerle J, Behr J, von Bergwelt-Baildon M, Reincke M, Grabein B, Hinske C L, Blum H, Keppler O T. Genomic epidemiology reveals multiple introductions of SARS-CoV-2 followed by community and nosocomial spread, Germany, February to May 2020. EuroSurveillance 26 (2021). https://doi.org/10.2807/1560-7917.ES.2021.26.43.2002066
Muenchhoff M, Mairhofer H, Nitschko H, Grzimek-Koschewa N, Hoffmann D, Berger A, Rabenau H, Widera M, Ackermann N, Konrad R, Zange S, Graf A, Krebs S, Blum H, Sing A, Liebl B, Wolfel R, Ciesek S, Drosten C, Protzer U, Boehm S, Keppler O T. Multicentre comparison of quantitative PCR-based assays to detect SARS-CoV-2, Germany, March 2020. EuroSurveillance 25 (2020). https://doi.org/10.2807/1560-7917.ES.2020.25.24.2001057
Muenchhoff M, Chung A W, Roider J, Dugast A S, Richardson S, Kloverpris H, Leslie A, Ndung'u T, Moore P, Alter G, Goulder P J R. Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection. mSphere 5 (2020). https://doi.org/10.1128/mSphere.00880-20
Muenchhoff M, Adland E, Roider J, Kloverpris H, Leslie A, Boehm S, Keppler O T, Ndung'u T, Goulder P J R. Differential Pathogen-Specific Immune Reconstitution in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Children. Journal of Infectious Diseases 219:1407-1417 (2019). https://doi.org/10.1093/infdis/jiy668
Muenchhoff M, Healy M, Singh R, Roider J, Groll A, Kindra C, Sibaya T, Moonsamy A, McGregor C, Phan M Q, Palma A, Kloverpris H, Leslie A, Bobat R, LaRussa P, Ndung'u T, Goulder P, Sobieszczyk M E, Archary M. Malnutrition in HIV-Infected Children Is an Indicator of Severe Disease with an Impaired Response to Antiretroviral Therapy. AIDS Research and Human Retroviruses 34:46-55 (2018). https://doi.org/10.1089/AID.2016.0261
Muenchhoff M, Adland E, Karimanzira O, Crowther C, Pace M, Csala A, Leitman E, Moonsamy A, McGregor C, Hurst J, Groll A, Mori M, Sinmyee S, Thobakgale C, Tudor-Williams G, Prendergast A J, Kloverpris H, Roider J, Leslie A, Shingadia D, Brits T, Daniels S, Frater J, Willberg C B, Walker B D, Ndung'u T, Jooste P, Moore P L, Morris L, Goulder P. Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection. Science Translational Medicine 8:358ra125 (2016). https://doi.org/10.1126/scitranslmed.aag1048
Payne R*, Muenchhoff M*, Mann J, Roberts H E, Matthews P, Adland E, Hempenstall A, Huang K H, Brockman M, Brumme Z, Sinclair M, Miura T, Frater J, Essex M, Shapiro R, Walker B D, Ndung'u T, McLean A R, Carlson J M, Goulder P J. Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. Proceedings of the National Academy of Science (PNAS) 111:E5393-400 (2014). https://doi.org/10.1073/pnas.1413339111
Muenchhoff M, Prendergast A J, Goulder P J. Immunity to HIV in Early Life. Frontiers in Immunology 5:391 (2014). https://doi.org/10.3389/fimmu.2014.00391
Muenchhoff M, Goulder P J. Sex differences in pediatric infectious diseases. Journal of Infectious Diseases 209 Suppl 3:S120-6 (2014). https://doi.org/10.1093/infdis/jiu232

Auszeichnungen

Auszeichnungen PD Dr. med. Maximilian Muenchhoff

  • 2018 Robert-Koch Postdoctoral Award in Virology (Robert-Koch-Stiftung e.V.)
  • 2017 Clinical leave Research Stipend (DZIF)
  • 2017 HIV/AIDS Research Award (Deutsche Gesellschaft für Infektiologie)