HIV immune activation and morphogenesis

The group of Michael Schindler investigates how the Human Immunodeficiency virus Type 1(HIV-1) and Hepatitis C virus (HCV) manipulate infected cells for efficient replication and immune evasion. We mainly focus on the morphogenesis of HIV-1 and HCV within living cells and examine the causes and consequences of HIV mediated manipulation of immune activation.

HIV-1 and HCV are major global health threads. Currently, more than 35 million people are HIV infected and annually around 2 million die of AIDS. HCV has a lethality of 5-10% with at least 130 million infected individuals worldwide. For HIV, and since 2011 also for HCV, there are specific antivirals approved for therapy which suppress viral infection and/or replication. However ongoing problems are the emergence of drug resistances caused by the high variability of both viruses. In addition, neither for HIV nor HCV a preventive vaccine is available.

Our group aims to unravel the mechanisms by which HIV-1 and HCV hijack and reprogram infected cells for efficient replication and immune evasion. In more detail, our goal is to monitor and thereby elucidate the steps of HIV-1 and HCV egress in living cells. For this, we develop viral genomes expressing chromophores in structural and regulatory genes and monitor virus trafficking by state-of-the-art imaging techniques in primary HIV-1 target cells and liver cells. These experiments are combined with the molecular manipulation of host cell factors by drugs or siRNAs in order to identify cellular pathways involved in virus morphogenesis and furthermore identify virus-host interactions which could represent novel therapeutic targets.

A second focus is to clarify the causes and consequences of HIV induced generalized immune activation. HIV-1 can infect resting T cells but needs to drive cellular activation for efficient viral gene expression and thus completion of the viral life cycle. HIV-1 has evolved mechanisms to induce and maintain an unspecific generalized activation of the immune system. The current concept of HIV/AIDS pathogenesis is that this immune activation results in increased T cell hyperproliferation and turnover. Ultimately, continuous T cell death leads to an exhaustion of the regenerative capacity of the immune system, loss of total T cell numbers and therefore AIDS. More specifically, we investigate the mechanisms by which HIV proteins induce unspecific generalized immune activation, but also how the virus manages to evade the specific innate and adaptive immune response of the host.