Institute for Medical Virology and Epidemiology of Viral Diseases

Cells are equipped with numerous antiviral factors that target essentially all steps of the viral replication cycle. While they constitute an important first line of defense and protect us against many invading (emerging) viral pathogens, some viruses have evolved effective mechanisms to evade or counteract these antiviral factors. One main focus of our research is the identification and characterization of previously undescribed host proteins that suppress viral replication. For example, our lab recently identified guanylate-binding proteins 2 and 5 (GBP2/5) as two interferon-inducible proteins that exert broad antiviral activity by inhibiting the proteolytic maturation of viral glycoproteins (Braun et al., 2019). Since GBP2 and GBP5 do not directly target viral pathogens, but inhibit the cellular protease furin, we are currently investigating potential off-target effects of this antiviral mechanism in infected cells.

The main model organisms of our lab are retroviruses such as human and simian immunodeficiency viruses (HIV‑1, HIV-2, SIVs), as well as coronaviruses (e.g. SARS-CoV-2). Despite their limited genome sizes, they manage to replicate and spread efficiently in their hosts. This is partly because many viral proteins are multifunctional and target several components of the antiviral immune response. For example, research in our lab revealed that the viral protein U (Vpu) of HIV-1 and SIV not only increases virus release by counteracting the restriction factor tetherin, but exerts much broader immuno-suppressive effects by inhibiting the activation of the transcription factor NF-κB (Langer et al., 2019; Hotter et al., 2017). In the absence of Vpu, NF-κB drives the expression of interferons and other antiviral factors. Furthermore, Vpu proteins of different groups of HIV-1 and several SIV species decrease the amount of HLA-C at the surface of infected cells to evade killing by cytotoxic T cells (Hopfensperger et al., 2020). Intriguingly, the second human immunodeficiency virus, HIV-2, that naturally lacks a vpu gene has evolved an independent mechanism to decrease HLA-C surface levels involving the viral infectivity factor Vif (Hopfensperger et al., 2020). Our current research aims at investigating how different coronaviral proteins modulate HLA levels and suppress interferon-mediated immune responses in infected cells.

Due to the ongoing tug-of-war between viruses and their hosts, antiviral host factors are among the fastest evolving proteins. As a result, they are only poorly conserved, and many of them pose important barriers to successful cross-species transmission events of viral pathogens. For example, our research revealed that the host restriction factor tetherin constitutes an important barrier to zoonotic transmission of simian immunodeficiency viruses to humans (Sauter et al., 2009; Sauter et al., 2010; Heusinger et al., 2018; Sauter and Kirchhoff, 2019). Nevertheless, some immunodeficiency viruses managed to adapt to their new human host and evolved mechanisms to efficiently counteract the human orthologue of tetherin. These viruses spread efficiently in the human population, resulting in the current HIV/AIDS pandemic. Thus, our findings provide important insights into the determinants of successful viral spread of zoonotic viruses in humans.

The human genome contains hundreds of thousands of so-called endogenous retroviral elements that represent remnants of past encounters with once infectious retroviruses. Although human endogenous retroviruses (HERVs) fail to produce infectious viral particles, they play key roles in several physiological and pathophysiological processes. While some of them may exert detrimental effects if their transcription is not effectively suppressed, others have been hijacked by the human organism. For example, accumulating evidence suggests that endogenous retroviral promoter and enhancer elements regulate the expression of a variety of cellular genes. In line with this, we could recently demonstrate that expression of the broadly antiviral factors GBP2 and GBP5 is driven by two endogenous retroviral promoters. Intriguingly, these retroviral promoter elements are activated in HIV-1 infected T cells (Srinivasachar Badarinarayan et al., 2020). Thus, our immune system exploits retroviral fossils in our DNA to regulate innate immune responses against HIV-1 and other viral pathogens.