Nucleic acid-binding proteins modulating viral infection and evolution
Our work focuses on understanding the role of cellular nucleic acid-binding proteins in viral infections. Nucleic acids (RNA and DNA) encode the genetic message of all pathogens and their hosts. Nucleic-acid-binding proteins perform important functions in cell homeostasis, play pro- and anti-viral roles, activate host immune responses and influence disease pathogenesis. Understanding the molecular basis of these functions will bring us closer to exploiting them as novel antiviral drug targets. Furthermore, studying the interplay between cellular proteins and viral genomes uncovers co-evolutionary dynamics between pathogens and their hosts. By understanding the impact of host proteins on viral genomes, we can define shared features of pandemic viruses. This knowledge of pandemic prerequisites can help to evaluate the risks associated with new pathogens and potentially predict future outbreaks. Thus, investigating how cellular nucleic acid-binding proteins interact with viruses provides valuable insights into virus biology and future evolution and aids the development of novel antivirals that disrupt viral replication, reduce viral load, or modulate host immune responses. Our current focuses include:
ZAP and nucleic acid-binding cellular proteins inhibiting viral infection
Viruses hijack cellular transcriptional and translational machineries to replicate. During this process, viral DNA and/or RNA interact with host nucleic acid-binding proteins, including immune sensors and antiviral effectors. One of them, the Zinc finger antiviral protein (ZAP) targets many human pathogens including HIV and SARS-CoV-2 by binding CpG dinucleotides in the viral RNA (Kmiec & Nchioua et al., 2020; Kmiec et al., 2021). Importantly, ZAP does not have catalytic activity and forms an antiviral complex with members of the cellular degradation machinery to destroy viral RNA. While the broad activity of ZAP and its relevant role in innate immunity is well documented, little is known about cellular mechanisms regulating its sensing and effector functions. We are currently studying the association between ZAP and RNA-degrading enzymes called ribonucleases, and investigating how cellular state modulates the activity and composition of the ZAP antiviral complex. Furthermore, we are also interested in other RNA-binding proteins acting as antiviral sensors and effectors, which can explain the differences in viral spread and pathogenesis and potentially be exploited in the context of new antiviral therapies.
Role of nucleic acid-binding proteins in viral evolution
The genomes of most human viruses contain low numbers of CpG dinucleotides to avoid restriction by ZAP. However, this evasion mechanism is not perfect as ZAP still binds remaining CpG dinucleotides and targets viral transcripts, especially during immune activation. Similarly to ZAP, APOBEC3 proteins bind viral genomes. This binding results in cytosine (C) deamination and mutations, which might have both positive and negative effects on the virus. HIV-1, HIV-2 and related monkey-infecting viruses use their Vif protein to actively degrade APOBEC3 proteins (Nchioua & Kmiec et al., 2021). HIV-1, SARS-CoV-2 and Monkeypox virus genomes all carry signatures of APOBEC3 editing (Jung et al., 2021; Kmiec & Kirchhoff, 2022), but it is still unknown if the last two also actively antagonize this process. We are interested in the long-term effects of ZAP and APOBEC3 proteins on viral evolution, especially in their role in the emergence of host-specific adaptations and immune or drug escape mutations.
Current members of the group: Lukas Kuhn (PhD student), Dr. Dorota Kmiec (Group leader), Linda Grabe (PhD student).
Recent Publications
Kmiec D*, Nchioua R*, Sherrill-Mix S, Sturzel CM, Heusinger E, Braun E, Gondim M, Hotter D, Sparrer KM, Hahn BH, Sauter D, Kirchhoff F. CpG Frequency in the 5' Third of the env gene determines sensitivity of primary HIV-1 strains to ZAP. mBio 2020;11(1) e02903-19. (*authors contributed equally)
DOI: 10.1128/mBio.02903-19
Kmiec D, Lista MJ, Ficarelli M, Swanson CM, Neil SJD. S-farnesylation is essential for antiviral activity of the long ZAP isoform against RNA viruses with diverse replication strategies. PLoS Pathog. 2021;17(10):e1009726.
DOI: 10.1371/journal.ppat.1009726
Nchioua R*, Kmiec D*, Gaba A, Sturzel CM, Follack T, Patrick S, Kirmaier A, Johnson WE, Hahn BH, Chelico L, Kirchhoff F. APOBEC3F Constitutes a Barrier to Successful Cross-Species Transmission of SIVsmm to Humans. J Virol. 2021;95(17). (*authors contributed equally)
DOI: 10.1128/JVI.00808-21
Kmiec D, Kirchhoff F. Monkeypox: A New Threat? Int. J. Mol. Sci. 2022, 23 (14), 7866.
DOI: 10.3390/ijms23147866
Jung C*, Kmiec D*, Koepke L*, Zech F*, Timo J, Sparrer KMJ, Kirchhoff F. Omicron: What makes the latest SARS-CoV-2 Variant of Concern so concerning? J Virol. 2022 Feb 28: jvi0207721. (*authors contributed equally)
DOI: 10.1128/jvi.02077-21