Research Areas

Human Immunodeficiency Virus (HIV) is a contemporary retrovirus that replicates through integration of proviral DNA into the genome of infected cells. This remarkable viral life cycle brings about several intriguing features. Integrated proviral sequences can be transcriptionally repressed, resulting in a latently infected reservoir that is hampering current efforts to eradicate HIV once infection has occurred. Furthermore, chronically HIV-infected patients accumulate a large number of defective proviral sequences within the genomes of HIV target cell. Very little is known to date about the impact of these sequences on host cell biology.

Particular emphasis also lies on analysis of broader changes in genome biology. To explore these, we study the regulation of human endogenous retroviral (HERV) elements in the context of HIV infection. These elements are derived from ancient retroviral infection events, which have left our genome covered with thousands of viral-derived sequences.

Crosstalk of proviral DNA with the human genome in chronic HIV infection

One of our goals is to improve our understanding of how the proviral integration site landscape is shaped in chronic HIV infection and in particular how this landscape contributes to proviral and cellular transcriptional regulation. Generally, we would like to understand how HIV proviral DNA integration impacts on host cell physiology.

We approach these questions in different ways. First, we are using bioinformatics approaches to gain a comprehensive overview of proviral integration site distribution and characteristics in chronic HIV infection. We compile data from multiple studies, which we submit to genome-wide analysis with particular emphasis on epigenetic and genetic features associated with proviral integration. Second, we employ a range of molecular biology techniques and make use of site-specific targeting technologies in order to generate suitable cellular model systems. Our focus is on the analysis of local and genome-wide epigenetic and transcriptional changes brought about by proviral integration. We also extend our work to primary cells derived from people living with HIV to probe our findings.

Overall, we expect our studies to promote our understanding of the biology of HIV infection and in particular of the impact of chronic infection on human host physiology. Eventually this understanding will be essential to optimize clinical approaches and therapeutic strategies.

Regulation of Human Endogenous Retroviruses (HERVs) in HIV infection and human disease

In addition to the contemporary retrovirus HIV, we also aim to understand how ancient retroviral elements in our genome, called HERVs, are regulated and function in the context of different pathological manifestations. State of the art methods now allow HERV-specific expression analysis and characterization of epigenetic profiles on a genome-wide level. Using NGS technology and adapted bioinformatic pipelines, we undertake HERV profiling coupled with integrative multiomics analysis for a more detailed view of regulatory HERV networks and the dynamics of HERV/human interactions.

Our primary focus are changes in HERV profiles upon acute and chronic HIV infection. In addition, we extend our work to HERV-mediated effects in a broader context, exploring further pathological states, such as for example malignant proliferation.

Development of cell-specific vectors for Gene and Immunotherapies in hematopoietic cells

Another part of our team works on next-generation viral vectors for gene therapy applications. We primarily focus on vectors targeting cells of the hematopoietic system in vivo, a niche that has lacked efficient gene delivery methods to date. We have demonstrated that the genetic engineering of Adeno-associated virus (AAV) capsid proteins with target cell-specific nanobodies (small antibodies derived from llamas) yields highly specific vectors compared to their natural serotype counterparts (PMID 34928979). By further developing these nanobody-AAVs, we expand this technological platform to different AAV serotypes, utilizing various hematopoietic and immune surface markers to specifically target different cell types. We evaluate their performance in comparison to natural serotypes in primary cell culture as well as in vivo humanized mouse models. These vectors potentially have broad applications in gene and immune therapeutic interventions.