HTLV-1 is a highly oncogenic yet neglected retrovirus, which primarily infects white blood cells (CD4+ T-cells) in vivo and causes incurable diseases like Adult T-cell leukemia (ATL) or inflammatory maladies like HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) after lifelong viral persistence. Worldwide, at least 5-10 mio people are HTLV-1-infected and most of them are unaware of their infection. Endemic regions are located in Japan, Central Australia, Melanesia, South America, the Caribbean and the Middle East. The virus is transmitted via cell-containing body fluids such as blood products, semen and breast-milk, which constitutes the major route of mother-to-child transmission. After infection of CD4+ T-cells, HTLV-1 is reversely transcribed and integrates into the host cell genome. Despite the high number of people worldwide living with a persistent HTLV-1 infection, there is still no efficient prevention strategy, vaccine or cure of HTLV-1 and its associated diseases.
Our central aims are to prevent HTLV-1 transmission and to develop strategies to lower the proviral load in infected patients. Our main research areas are:
- Transmission of retroviruses by breast milk and development of prevention strategies
- Molecular insights into HTLV-1-transmission and cell-cell-communication
- Interfering with HTLV-1 transcription to enhance immunogenicity of HTLV-1
- Impact of viral proteins on the cellular transcriptome
- Tumor induction and interplay with the tumor microenvironment
We are happy to announce that the federal Ministry of Education and Research (BMBF) supports our work by funding of a Junior Research Group in Infection Research. Within the project Milk-TV, which is short for “Milk Transmission of Viruses”, we seek to explore early events of HTLV-1 transmission and to develop prevention strategies to fight HTLV-1-infections. Briefly, breastfeeding is recommended by the World Health Organization for at least 6 months and up to 2 years of age, and it is proven that breast milk protects against several diseases and viral infections. Intriguingly, few viruses are preferentially transmitted via breastfeeding including HTLV-1. Risk of transmission increases with the duration of breastfeeding, however, abstinence from breastfeeding is not an option in resource-limited settings or underrepresented areas or populations. Despite significant progress in understanding details of cell-to-cell transmission, it is still unclear, which cells in which organs get infected via the oral route, how these cells get infected, how breast milk affects this route of infection and how to inhibit oral transmission despite breastfeeding, which is an urgent need especially in underrepresented areas of the world (Millen and Thoma-Kress, 2022). Thus, we strive within this project to address these questions experimentally with the help of different tissue culture model systems and the development of strategies to block HTLV-1 transmission. Overall, our central aim is to uncover prevention strategies that might ultimately allow infants to benefit from breastfeeding while reducing the risk of HTLV-1 transmission.
Transmission of HTLV-1 to other cells is strictly dependent on cell-cell contacts and viral particles are transferred to other cells after polarized budding at a tight and confined cell-cell contact, the so-called virological synapse. We found that the actin-bundling protein Fascin, which is transcriptionally-induced by the viral Tax protein, is crucial for HTLV-1 cell-to-cell transmission (Gross et al., 2016; Mohr et al., 2015; Heym et al., 2022). Repression of Fascin not only impaired release of viral particles, but also cell-to-cell transmission in different model systems. Imaging revealed that Fascin’s localization at tight cell-cell contacts is accompanied by polarization of the Gag proteins, suggesting that Fascin directly affects the distribution of Gag to budding sites, and therefore, viral transmission (Gross et al., 2016; Wiesmann et al., 2016).
HTLV-1 transmission may also occur via viral biofilms at virological synapses, an agglomeration of viruses that are packaged on top of the infected cells in a microbial biofilm-like structure. Our work shed further light on the composition of theses viral biofilms. Based on transcriptomics and data mining, we found that the structural protein Collagen IV (COL4A1/ COL4A2) is transcriptionally regulated by Tax and a component of viral biofilms, with COL4A2 appearing to impact virus transmission. Thus, our study provided first links between Tax’s activity and formation of the viral biofilm by hijacking COL4 protein functions (Millen et al., 2019).
HTLV-1 is not only transmitted at tight cell-cell contacts, rather, transmission may also occur via long-distance connections, which are induced by the small accessory viral protein p8. This protein is generated by proteolytic cleavage from the precursor p12 encoded on open reading frame I of the HTLV-1 genome. p8 induces cellular protrusions and is transferred to other cells to foster HTLV-1 cell-to-cell transmission. To get molecular insights into p8 transfer and HTLV-1-transmission, we made use of bioinformatics in combination with proteomics. Our studies identified novel interaction partners of p8, amongst them vasodilator stimulated phosphoprotein (VASP). After having developed a novel flow cytometry-based assay which allows rapid and automatic quantitation of p8 transfer to target cells (Donhauser et al., 2018), we could show that knockout of VASP delays the transfer of p8 between cells, most likely by impairing recruitment of p8 to the plasma membrane (Donhauser et al., 2020). Importantly, this study revealed that VASP is also important for HTLV-1 cell-to-cell-transmission (Figure 1).
The viral transactivator Tax stimulates viral replication by recruiting host cell factors like positive transcription elongation factor b (p-TEFb) to the viral promoter and by enhancing mitotic expansion of infected cells. Since viral gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, new therapeutic strategies aim to transiently activate viral gene expression to shift the equilibrium in favor of an enhanced CTL response to enhance immunogenicity of HTLV-1 Tax, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Thus far, the composition of the protein complex guiding viral gene expression is only partially understood and systematic analyses and comparisons of compounds affecting viral transcription are lacking (Schnell et al., 2021). Thus, we systematically screened HDAC-inhibitors for their potential to enhance HTLV-1 transcription. We found that Romidepsin and Panobinostat are promising compounds to raise viral transcription (Schnell et al., 2022). In earlier work, we could identify strong and specific upregulation of the transcription elongation factor ELL2 in HTLV-1-infected cells (Mann et al., 2014). We found that ELL2 strongly enhances Tax-mediated transactivation of the HTLV-1 promoter, and that ELL2 and Tax are part of a common protein complex. However, the detailed composition of this complex and its impact on viral reactivation are unclear. Now, we could shed more light on Tax:ELL2 complex formation (Kohrt et al., 2021), and we currently analyse strategies to interfere with HTLV-1 transcription and to enhance immunogenicity of HTLV-1.
Our lab has a long-lasting interest in how viral proteins modulate the cellular transcriptome. In earlier studies, we focused on signaling induced by the viral Tax-1 protein and could identify novel cellular target genes of Tax that are crucial for virus transmission, cellular proliferation and invasive migration (Kress et al., 2011; Gross et al., 2016; Millen et al., 2019). In a current project we use state-of-the art sequencing techniques to analyze the impact of viral proteins on early events in the cellular transcriptome upon infection of primary cells. These studies will help to provide a better understanding of how HTLV-1 impacts the transcriptomes of the target cells upon de novo infection, thus, providing novel insights into HTLV-1’s capacity to perturbate of T-cell signaling.
Meilenstein im Kampf gegen Auslöser einer Form der Leukämie. 28.03.2023.
Neue FAU-Nachwuchsgruppenleiterin: Dr. Andrea Thoma-Kreß. 30.3.2021.
Unsere FAU-Nachwuchsgruppenleitungen. 30.3.2021
Unsere FAU-Nachwuchsgruppenleitungen | Friedrich-Alexander-Universität Erlangen-Nürnberg
Wege in die Wissenschaft. 24.2.2021. FAU-Magazin “Friedrich”.
Virus im Fokus. Infektionsforschungsprojekt profitiert von Nachwuchsgruppenförderung durch das BMBF. 16.11.2021.
Der Weg ist das Ziel. Ampuls 3/2020, Seite 7. Zeitung für alle Mitarbeitenden des Uni-Klinikums Erlangen.
Auszeichnung für herausragende Grundlagenforschung zur Tumorentstehung. 5.10.2017.