Unraveling epigenetic and metabolic interplay during cell fate transition of HIV-1 infected T cells

• Applicant: Dr. Marina Lusic, Ph.D.
• Subject Area: Immunology ; Virology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455044444

Human Immunodeficiency Virus 1 (HIV-1), the causative agent of acquired immune deficiency syndrome (AIDS), hijacks the cellular machinery of T Cells to facilitate its replication. The existence of HIV-1 latently infected cells with stably integrated, transcriptionally repressed, but replication competent proviruses represents the major roadblock to eradicating the infection under current antiretroviral therapy (ART). Once therapy is interrupted, the virus emerges from latency, and viral replication and spread are re-established within weeks. How HIV-1 establishes latent infection in memory CD4+ T cells is still a matter of debate. The most likely scenario is the one according to which infected activated CD4+ T cells revert to a resting memory state where latency is established as a result of changes in cellular metabolism and decreased viral gene expression. Elucidating metabolic changes that shape cellular response to infection and the impact of these metabolic changes on chromatin structure and viral gene expression are a prerequisite towards a complete understanding of HIV-1 latency mechanisms.The research herein proposed builds on a set of our recently published and preliminary data revealing important new insights into nuclear organization processes following T cellular differentiation and transition to HIV-1 transcriptional latency. The main focus is on understanding how T cell activation and/or viral infection induced changes of cellular metabolism affect their chromatin states, specifically at HIV-1 integration sites, to either promote viral replication or to accompany cell fate transition and establishment of proviral latency. As part of the long sought goal of understanding the complex epigenetic and metabolic background of HIV-1 host cells, we will use our expertise in molecular virology, single-cell high-throughput microscopy and genomics approaches, including HIV-1 integration site sequencing, to address these pivotal questions that could help also in further developments towards a functional HIV-1 cure.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Bojana Lucic, Ph.D.