Project A01

Principal Investigator

Prof. Dr. Jens Bosse

CSSB Center for Structural Systems Biology
Hannover Medical School
RESIST group Quantitative Virology

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PhD candidate

Julian Kraft

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Project Summary

Analysis of in-silico-predicted protein-protein interactions involved in herpes simplex virus 1 genome packaging. 

Herpes simplex virus 1 (HSV-1), a structurally complex and globally widespread member of the herpesvirus family, establishes lifelong latency in human sensory neurons upon primary infection, from where it can periodically reactivate to resume lytic replication. While lytic infections are typically self-limiting, immunodeficient patients are disproportionately affected by more severe and potentially life-threatening manifestations, including hepatitis, esophagitis, and encephalitis. During primary and recurrent infection cycles, HSV-1 replicates and packages its linear double-stranded DNA genome into preformed procapsids in the host cell’s nucleoplasm before egressing from the nucleus for further maturation and being released at the plasma membrane in the form of infectious enveloped virions1,2.

In a collaborative effort, at least seven viral proteins, including pUL6, pUL17, pUL25, and pUL32 as well pUL15, pUL33, and pUL28, comprising the terminase complex, mediate specific steps of viral genomic DNA packaging. Their assembly into higher-order complexes and their interaction amongst each other are essential to carry out their function and any disturbances in these processes lead to a failure of viral genome packaging into capsids3.
To better understand how these proteins mediate HSV-1 genome packaging we employ an integrative approach by combining in-silico-based protein structure prediction tools, such as AlphaFold-Multimer, with wet lab-based in-vitro– and in-vivo-assays4 (Figure).
We aim to identify and functionally characterize the protein complexes involved in HSV-1 genome packaging and furthermore resolve their spatiotemporal interaction patterns in infected cells. These results can ultimately serve as the basis for developing more targeted and effective therapeutic interventions, which are particularly crucial for managing vulnerable patient cohorts and patients infected with resistant herpesvirus strains5.

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References

  1. James C, Harfouche M, Welton NJ, et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020;98(5):315-329. doi: 10.2471/BLT.19.237149
  2. Whitley RJ, Roizman B. Herpes Simplex Viruses. In: Clinical Virology. ASM Press; 2016:415-445. doi: 10.1128/9781555819439.ch20
  3. Heming JD, Conway JF, Homa FL. Herpesvirus Capsid Assembly and DNA Packaging. In: Osterrieder K, ed. Cell Biology of Herpes Viruses. Vol 223. Advances in Anatomy, Embryology and Cell Biology. Springer International Publishing; 2017:119-142. doi: 10.1007/978-3-319-53168-7_6
  4. Evans R, O’Neill M, Pritzel A, et al. Protein Complex Prediction with AlphaFold-Multimer. bioRxiv; 2021. doi: 10.1101/2021.10.04.463034
  5. Andrei G, Snoeck R. Herpes simplex virus drug-resistance: new mutations and insights. Current Opinion in Infectious Diseases. 2013;26(6):551-560. doi: 10.1097/QCO.0000000000000015