# Arif Enes Karaca (Herpesviruses)

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## Introduction

* **Human herpesviruses belong to the family Herpesviridae, they are ubiquitous viruses and once the first infection occurs, they remain in the body of the affected individual during the lifetime. These viruses cause a wide variety of diseases, and infections are often benign, but may in immunocompromised individuals cause clinical manifestations with different level of severity.**

* **The Herpesviridae family is divided into 3 subfamilies: Alphaherpesvirinae (α-herpesvirinae), Betaherpesvirinae (β-herpesvirinae) and Gammaherpesvirinae (γ-herpesvirinae). These are distinguished by their viral and structural characteristics, as well as by their pathogenic potential. All types of viruses classified into this family are double-stranded DNA viruses and the different types of herpes viruses share similar structural characteristics.[1]**

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## The Human Herpesviruses


#### Figure 1. Members of the human herpesvirus family[1]

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## Herpesvirus simplex 1 and 2

* **Human herpesviruses type 1 and 2 (HSV-1 and HSV-2) are usually associated with herpes and genital herpes, respectively. However, genital herpes may be a consequence of HSV-1 infection and cold sores may also be caused by HSV-2. Once the individual has been infected, reactivation is extremely common in both clinical forms: oral or genital. The lesions are bullous and painful although it tends to disappear in a few intervals of time.[2]**

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## Varicella-zoster virus

* **Human herpesvirus type 3 (Varicella-zoster) causes varicella (chickenpox) in a primary infection that occurs especially in children and reactivation can cause the onset of zoster that is more frequent in the elderly. Neurologic zoster is an important complication of this infection, especially in elderly and immunosuppressed patients.[2]**

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## Epstein-Barr virus

* **Human herpesvirus type 4 (Epstein-Barr virus; EBV) is associated with infectious mononucleosis, Burkitt’s lymphoma, and nasopharyngeal carcinoma. The most important aspect of EBV is its oncogenic potential. A majority of cases of EBV infection have a low impact on the individual; however, a complication such as hepatitis, lymphoproliferative syndrome, and encephalitis can rarely occur.[2]**

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## Cytomegalovirus

* **Primary cytomegalovirus infection causes a “mononucleosis-like syndrome” known as cytomegaly or “cytomegalic inclusion disease.” Cytomegalovirus is not well known by the general public because it causes often not severe clinical conditions. The impact of cytomegalovirus infection HIV-infected and transplant patients is well recognized.[2]**

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## Human herpesviruses 6 and 7

* **Primary HHV-6 and HHV-7 infections cause a common early febrile infectious syndrome known as roseola infantum or exanthem subitum. The HHV-6 has been related to transplant rejection and graft-versus-host disease in bone marrow transplantation.[2]**

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## Human herpesviruses 8

* **Human herpesvirus type 8 is associated with Kaposi’s sarcoma and can lead to death in immunosuppressed patients, especially acquired immunodeficiency syndrome (HIV/AIDS).[2]**

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## Herpesvirus virion

* **The herpes virus virion is composed of an icosahedral capsid containing the double-stranded DNA genome, a lipid envelope decorated with virally encoded glycoproteins, and a layer filled with proteins termed the tegument which resides between the capsid and the envelope. The likely sites for packaged coding and non-coding RNAs are the tegument and the capsid. There is evidence for RNA–protein interactions in the tegument, but it is unclear whether all packaged RNAs interact with tegument proteins. Although it is possible, we are unaware of evidence for protein–RNA interactions in the nucleus, or RNA–RNA interactions in either the nucleus or tegument.[3]**


#### Figure 2. Schematic of herpesvirus virion[3]

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## Herpesvirus Genome Organization

* **The genomes of herpesviruses are composed of varying number of unique and repeat regions. The replication origins can be located either in the unique, or in the repeat regions, or in both.[4]**


#### Figure 3. The genomic structure of various herpesviruses[4]

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## The Entry and Attachment Mechanism of Herpesviruses


#### Figure 4. Model of the herpesvirus entry mechanism[5]

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## Transcription, Translation, and DNA replication


#### Figure 5. Life cycle of herpesviruses[6]

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## The packaging and assembly

* **After genome replication, the DNA packaging step occurs and ends with the cleavage of the concatemers (represented by the double-ended black arrow), releasing viral DNA into the capsid. Different capsid forms are present in the host cell nucleus during infection. These capsid forms, referred to as A-, B- and C-capsids, represent empty capsids, scaffold- containing capsids and viral DNA-containing capsids, respectively. The C-capsids are considered as a precursor of infectious virus.[7]**


#### Figure 6. Different virus-like particles during the viral cycle of herpesviruses[7]

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## The Bioengineering applications of Herpesviruses

* **Herpes simplex virus has been reported to inhibit tumour necrotic factor (TNF) alpha NF-kB activation of genes involved in inflammatory response. TNF-α is a cytokine vital in innate immunity and, upon synthesis, induces the expression of genes involved in the inflammatory response. TNF-α binds its receptor TNF-R1 recruiting the adapter protein TNF receptor death domain (TRADD), which then recruits TNFR-associated factor 2 (TRAF2) and receptor- interacting protein 1 (RIP1) to the complex. TRAF 2 modulation of K63-based poly-ubiquitination of RIP1 brings about TGF-β-activated kinase-1 (TAK1), turning on the kinase activity of IκB kinase (IKK) which phosphorylates and degrades IκBα, subsequently leading to the activation of the nuclear factor kappa B (NF-κB), a transcriptional factor.**

* **However, HSV-1 γ134.5 protein (late gene encoded) represses NF-κB activation in CD8+ dendritic cells. Furthermore, a tegument protein, VHS, has also been reported to inhibit the viral replication independent NF-κB activation. A HSV-1 protein, UL42, that enhances the processivity of the DNA polymerase, inhibits the TNF-α dependent NF-κB activation. It was found out that UL42 binds the p65 and p50 subunits of NF-κB and inhibits their translocation into the nucleus. This will repress the transcription of genes involved in inflammatory reactions.[8]**


#### Figure 7. Cytosolic DNA sensing and pathway activation[8]

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## References:
1. R. L. Thomasini, Introductory Chapter: Human Herpesvirus - A Short Introduction. IntechOpen, 2020. doi: 10.5772/intechopen.89557.
2. Y. Kawaguchi, Y. Mori, and hiroshi kimura, Eds., Human Herpesviruses. Springer Singapore, 2018. doi: 10.1007/978-981-10-7230-7.
3. M. Amen and A. Griffiths, “Packaging of Non-Coding RNAs into Herpesvirus Virions: Comparisons to Coding RNAs,” Frontiers in genetics, vol. 2, p. 81, Nov. 2011, doi: 10.3389/fgene.2011.00081.
4. Z. Boldogkői, Z. Balázs, N. Moldován, I. Prazsak, and D. Tombácz, “Novel Classes of Replication-associated Transcripts Discovered in Viruses,” RNA Biology, Jan. 2019, doi: 10.1080/15476286.2018.1564468.
5. S. A. Connolly, T. S. Jardetzky, and R. Longnecker, “The structural basis of herpesvirus entry,” Nat Rev Microbiol, vol. 19, no. 2, Art. no. 2, Feb. 2021, doi: 10.1038/s41579-020-00448-w.
6. S. Zimmerli, “Immunology of viral disease, how to curb persistent infection,” Jun. 2021.
7. C. Muller, S. Alain, T. Baumert, G. Ligat, and S. Hantz, “Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses,” Life, vol. 11, p. 150, Feb. 2021, doi: 10.3390/life11020150.
8. A. C. Ike, C. J. Onu, C. M. Ononugbo, E. E. Reward, and S. O. Muo, “Immune Response to Herpes Simplex Virus Infection and Vaccine Development,” Vaccines, vol. 8, no. 2, Art. no. 2, Jun. 2020, doi: 10.3390/vaccines8020302.

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