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The research group "Innate Immunity and Viral Evasion" is interested in gaining a better understanding of the interplay between host cells and viruses at the cellular and molecular level.
HIV-1, the causative agent of AIDS, remains one of the most devastating viral pathogens worldwide and causes chronic immunodeficiency. Using human target cells of HIV-1, we characterize their ability to sense, with the help of the cellular pattern recognition receptors, an invading HIV-1 infection, and how efficiently this information translates into a functional antiviral state. Vice versa, we identify and elucidate HIV-1-mediated evasion strategies of this cellular innate immunity, which explain why HIV-1 is successfully circumventing cellular defense mechanisms. Furthermore, we investigate the mode of action of cellular restriction factors, focusing on the antiviral proteins 90K and SERINC5, which can reduce the infectivity of HIV-1 particles. Knowledge on these naturally occurring molecular weapons of human cells, and how HIV-1 has evolved to counteract them, could pave new avenues towards antiviral drugs. In addition, we are developing strategies for eradication of latently HIV-1-infected resting T-cells.
We are also investigating the early processes of Chikungunya virus infection and the innate immune responses during the infection. Chikungunya virus is an emerging and rapidly expanding pathogen which causes an acute, self-limiting infection in most cases. A subset of infected persons, however, suffers from chronic joint pain and inflammation, justifying research to develop protective and/or therapeutic options which are completely missing to date. Using both infectious particles and pseudotyped vectors, we aim to study immunological restriction as well as the entry process and replication of the virus.
Alumni: Irina Beukman (wiss. Hilfskraft | jetzt: Veterinärmedizin-Studentin an der Tiermedizinischen Hochschule Hannover), Sandra Dapa (Masterstudentin | jetzt: Research & Development, Miltenyi Biotech, Bergisch Gladbach), Aurélie Ducroux (Postdoktorandin | jetzt: Begutachterin für Qualitätskontrolle, COFRAC, Paris), Carina Elsner (Postdoktorandin), Sergej Franz (Doktorand | jetzt: Postdoktorand am Blood Systems Research Center, San Francisco), Nils Kriedemann (Praktikant | jetzt Masterstudent Biomedizin, Medizinische Hochschule Hannover), Veronika Lodermeyer (Doktorandin | jetzt: Remote Site Monitor, München), Anne Schnepf (wiss. Hilfskraft | jetzt: Praktikantin, Falkenklinik, Abu Dhabi), Kristina Suhr (MTA | jetzt: Studierende an der Universität Jena), Shuting Xu (Postdoktorandin)
DZIF- HIV Reservoir - Regulators of HIV persistence and reactivation, https://www.dzif.de/en/remission-and-cure, since 2021
Within the "HIV Reservoir" project of the TTU-HIV, our group contributes to the investigation of cellular and viral mechanisms of HIV-1 persistence, latency and reactivation, and to the development of strategies that identify and reduce the HIV-1 reservoir. To this end, we conduct single-cell-based analyses of CD4+ T-cells from HIV-1 positive individuals and HIV-1-negative controls, including single-cell RNA sequencing and chromatin accessibility assays. Specifically, we are investigating qualitative and quantitative changes at the cellular and viral level that are induced upon ex vivo treatment with latency-reversing agents. A better understanding of these processes is essential to advancing HIV-1 cure strategies.
HIV-1 Elite Controllers
HECTOR Foundation - Deep dive into the cellular milieu of HIV-1 elite controllers:
Analysis of basal cellular state and susceptibility to HIV-1 reactivation, https://www.hector-stiftung.de/medizinische-forschung/aidsforschung/m2101, since 2021
Elite controllers of HIV-1 infection maintain viral loads below the limits of detection and stable CD4+ T-cell counts, sometimes over years, despite the absence of antiretroviral therapy. Concerning the development of HIV-1 cure strategies, the hallmarks of these individuals are particularly valuable, providing a close approach to natural HIV-1 cure mechanisms. The phenomenon of elite control is rare and applies to less than 0.5% of HIV-1-infected individuals. Within this project, we team up with Prof. Clara Lehmann, University Hospital Cologne, and Prof. Dr. Julian Schulze zur Wiesch, UKE, in order to characterize cellular correlates of natural HIV-1 control in blood cells and gut-associated lymphoid tissue from HIV-1 elite controllers. Our work also addresses the susceptibility of latently infected cells from elite controllers to HIV-1 reactivation and the cellular characteristics of reactivating T-cells. We are applying state-of-the-art single cell analysis technologies, ultrasensitive HIV-1 p24 capsid ELISA-based and flow cytometric quantification of the translation-competent HIV-1 reservoir. A better understanding of cellular correlates to natural HIV-1 control will pave the way towards improved functional HIV-1 cure approaches.
Alphavirus infections: From cells over organisms to populations
DFG/ANRS COALITION - From cells over organisms to populations - Characterization of outcomes of emerging alphavirus infections (Project PIs: Drexler and Goffinet (both Charité, Berlin); de Lamballerie (Aix Marseille Université); Meertens (Inserm, Paris), since 2021
Alphaviruses cause severe acute and chronic disease in humans, including long-term debilitating arthralgia in the case of Chikungunya virus (CHIKV). In Latin America, CHIKV meets two broadly distributed, likely expanding, antigenically related autochthonous alphaviruses, namely Mayaro virus (MAYV) and Una virus (UNAV). The alphaviral immune interplay is poorly understood, challenging imminent alphavirus vaccination programmes. Within COALITION, in a team with Prof. Felix Drexler, Prof. Xavier de Lamballerie and Dr. Laurent Meertens, we are investigating alphavirus immune interplay and epidemiology at the level of individual cells, whole organisms and populations. At the level of cells, our group is deciphering the characteristics of alphaviral infections, analyzing the cellular state and cell-intrinsic innate immune responses and studying the impact of antibodies on infection. At the level of whole organisms, COALITION is assessing immune enhancement in patients acutely infected with CHIKV by analyzing their alphaviral immune background. At the population level, we are investigating community protective immunity potentially preventing CHIKV emergence by seroprevalence studies, geospatial modelling and phylogeographic reconstructions. The results of COALITION have the potential to profoundly enhance the understanding of alphaviral pathogenesis and spread and may impact vaccine programmes against these emerging threats for human health.
Cellular Restriction Factors of HIV-1 Infection
After recognition of pathogen-associated molecular patterns (PAMPs) by infected cells, interferons are synthesized, secreted and bind the interferon receptor on neighboring cells to „alarm“ them from an upcoming virus invasion. Binding induces a signaling cascade that ultimately results in synthesis of several interferon-stimulated genes, so-called ISGs (“interferon-stimulated genes”). One of those antiviral ISGs is lgals3bp, which encodes for the cellular glycoprotein 90K. Previous work of our group demonstrated the antiviral potency of 90K against HIV. Specifically, 90K reduces the infectivity of newly assembled virions by interfering with the viral incorporation of HIV Envelope proteins (Lodermeyer et al., Retrovirology 2013). Using truncated versions of 90K, we defined which domains/regions within 90K are essential and sufficient for its antiviral function. In parallel, 90K orthologs from non-human species, which share a high degree of homology with human 90K, but differ in their antiviral capability, are useful tools for the elucidation of the antiviral mechanism. Further, they shed light on the evolutionary conservation of 90K´s antiviral function (Lodermeyer et al., Journal of Virology 2018). The long-term perspective is to pave avenues towards a new antiviral treatment strategy.
SERINC5, another ISG-encoded protein, reduces the infectivity of HIV-1 particles by interfering with the fusogenicity of HIV-1 Env glycoproteins. The accessory protein HIV-1 Nef counteracts the antiviral effect of SERINC5. Via CRISPR/Cas9-mediated gene editing, we created T-cell lines expressing serinc5 alleles bearing a knocked-in HA-coding sequence. Using this unique tool, we study basic characteristics of endogenous SERINC5 expression and modes of Nef-mediated antagonism. A better understanding of SERINC5 restriction helps to identify vulnerable steps of the HIV-1 replication cycle, which may be targeted therapeutically.
Characterization of the functionality of the cGAS-mediated DNA Sensing Pathway in HIV-1-infected T-Cells
Upon HIV-1 infection of T-cells, viral DNA can be sensed by the cytosolic DNA sensor cGAS. In cocultures with macrophages, HIV-1 Env-mediated membrane fusion pores allow the horizontal transfer of the cGAS product and cyclic dinucleotide cGAMP to macrophages, where it activates STING-dependent expression of antiviral cytokines and effector molecules (Xu und Ducroux et al., Cell Host & Microbe 2016). In monocultures of T-cells and macrophages, HIV-1 prevents or counteracts activation of this cellular defense mechanism. In contrast to the situation in macrophages, our understanding of the reasons for the lack of a detectable type I IFN response in HIV-1-infected T-cells is limited. In this project, we address the effectiveness of the cGAS-mediated DNA sensing pathway in primary T-cells and try to unravel potential explanations for the lack of IFN induction in this important HIV-1 target cell type.
Mechanisms of Cell Entry and Immunologic Restriction of Chikungunya Virus
German/African DFG Cooperation Project with Dr. Eduardo Samo Gudo, NIH Maputo, Mozambique, since 2018
Chikungunya virus (CHIKV) is an emerging pathogen which spread from Africa to other tropical and subtropical regions worldwide, but also to colder areas such as southern Europe. Due to its ability to cause acute symptoms such as high fever, but also chronic suffering such as severe arthritic joint pain, specific treatments and prophylactic options need to be established. Therefore, we aim to study the cell attachment and entry process as well as cellular restriction by antiviral proteins and interferon stimulated genes. Using functional assays and confocal live cell imaging in a primary cell model of ex vivo-CHIKV infection, we dissect the steps of the infection from the binding to the host cell to the production of new viral particles and study virus-induced immunity responses. Together with Dr. Eduardo Samo Gudo, NIH Maputo, Mozambique, we are investigating the genetic variability of CHIKV and searching for immunological and genetic correlates of chronicity and convalescence in infected patients. Finally, in cooperation with Prof. Eike Steinmann (TWINCORE and University of Bochum) we are investigating the stability of CHIKV and testing disinfection methods for inactivation CHIKV (Franz et al., Journal of Infectious Diseases, 2018).
Development of novel preventive strategies against Chikungunya Virus Infection
Helmholtz/EU-Partnering Consortium MCMVaccine, since 2018
In an international team with scientists from the Helmholtz Center of Infection Research, Braunschweig, from TWINCORE, Hanover, and University Rijeka and University Zagreb, Croatia, we develop and validate CMV-based vaccine vectors against Chikungunya virus infection.
A complete list of all our publications can be found here.
Some selected articles are indicated here:
The barrier functions of crude cervical mucus plugs against HIV-1 infection in the context of cell-free and cell-to-cell transmission, AIDS, 2021, https://journals.lww.com/aidsonline/Abstract/9000/The_barrier_functions_of_crude_cervical_mucus.96362.aspx
Human IFITM3 restricts Chikungunya virus and Mayaro virus infection and is susceptible to virus-mediated counteraction, Life Science Alliance, 2021, https://www.life-science-alliance.org/content/4/7/e202000909
Mild COVID-19 despite autoantibodies to type I IFNs in Autoimmune-Polyendocrine-Syndrome Type 1 (APS-1), Journal of Clinical Investigation, 2021, https://www.jci.org/articles/view/150867
- Absence of cGAS-mediated type I IFN responses in HIV-1-infected T cells, Proceedings of the National Academy of Sciences USA, 2020, https://www.pnas.org/content/early/2020/07/23/2002481117.long
- COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis, Nature Biotechnology, 2020, https://www.nature.com/articles/s41587-020-0602-4
- Alert from a Distant Neighbor: Spread of Antiviral Immunity through Anion Channels (Preview Article), Immunity, 2020, https://www.sciencedirect.com/science/article/abs/pii/S1074761320301758?via%3Dihub
- Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor, Journal of Virology, 2019, https://www.ncbi.nlm.nih.gov/pubmed/31597782
- Susceptibility of Chikungunya Virus to Inactivation by Heat and Commercially WHO-Recommended Biocides, Journal of Infectious Diseases, 2018, https://www.ncbi.nlm.nih.gov/pubmed/29917109
- The Antiviral Activity of the Cellular Glycoprotein LGALS3BP/90K is Species-Specific, Journal of Virology, 2018, https://www.ncbi.nlm.nih.gov/pubmed/29743357
- cGAS-mediated innate immunity spreads intercellularly through HIV-1 Env-induced membrane fusion sites, Cell Host & Microbe, 2016, https://www.ncbi.nlm.nih.gov/pubmed/27736643
- 90K, an interferon-stimulated gene product, reduces the infectivity of HIV-1, Retrovirology, 2013, https://www.ncbi.nlm.nih.gov/pubmed/24156545
- HIV-1 antagonism of CD317 is species specific and involves Vpu-mediated proteasomal degradation of the restriction factor, Cell Host & Microbe, 2009, https://www.ncbi.nlm.nih.gov/pubmed/19286137
- HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription, Proceedings of the National Academy of Sciences USA, 2007, https://www.ncbi.nlm.nih.gov/pubmed/17209012
Prizes and Awards
- 10/2017-07/2018: DAAD PhD Stipend (Baxolele Mhlekude)
- 09/2017: DZIF/DGI Dissertation Prize 2017 (Shuting Xu)
- 06/2017: German AIDS Award 2017 of the German Society for AIDS (Shuting Xu, Aurélie Ducroux und Christine Goffinet)
- 05/2017: Daniel Wolf Prize 2017 of the Cold Spring Harbor Retroviruses Meeting (Shuting Xu)
- 07/2015-04/2016: Postdoctoral fellowship of the Ernst & Margarete Wagemann Foundation (Aurélie Ducroux)
- 03/2015: Poster Prize 2015 of the Society for Virology (Shuting Xu)
- 10/2014-03/2015: DAAD Stipend (Baxolele Mhlekude)
- 09-10/2013: Travel Grant from the Boehringer Ingelheim Fonds (Aparna Ponnurangam)
- 06/2013-10/2013: Habilitation Fellowship from the Margarethe von Wrangell-Program (initially granted funding period 5 years, ended 10/2013 due to move to Hanover) (Christine Goffinet)
- "Postdoktoranden-Preis 2012" for Virology of the Robert-Koch-Foundation (Christine Goffinet)
- 06/2012-06/2015: PhD fellowship according to the Landesgraduiertengesetz (Veronika Lodermeyer)
- "Wolfgang-Stille-Award 2010" of the Paul-Ehrlich-Society for Chemotherapy (Christine Goffinet und Oliver Keppler)
- 01/2010-10/2010: Postdoctoral Fellowship of the medical Faculty of the University Heidelberg (initially granted funding period 2 years, ended 10/2010 due to move to Ulm) (Christine Goffinet)
- 01/2008-12/2009: Postdoctoral Fellowship of the Peter und Traudl Engelhorn Foundation (Christine Goffinet)
- "Hygiene-Preis 2007" of the Rudolf-Schülke-Foundation (Christine Goffinet und Oliver Keppler)
- "AIDS-Forschungspreis 2007" of the German Society for Infectiology (Christine Goffinet und Oliver Keppler)