Herpesviridae

Herpesviruses (from Greek herpein=creep) are complex, human-pathogenic, host-specific, enveloped, double-stranded DNA viruses, which are equipped with an icosahedral capsid (protein envelope consisting of triangular faces), each of which is still surrounded by an envelope membrane. The genome of HSV, with about 150kb, is one of the large genomes of human pathogenic viruses. Between the envelope and the capsid are the tegument proteins, which have matrix-like properties as well as regulatory functions in viral replication. The envelope contains 12 different glycoproteins, which are responsible for absorption, penetration of the virus, but also for interactions with proteins of the immune system.

Herpesviruses are widely distributed in vertebrates and humans. It is assumed that about 85% (50-95%) of the population worldwide is infected with HSV-1 and 25% (5-50%) with HSV-2. However, there are no reliable figures for Germany or worldwide. About 30% of infected persons have recurrent infections and about 1% of virus carriers suffer frequent, i.e. 1 time/month, flare-ups of latent herpes infection.

Transmission: Alpha-herpesviruses usually first infect epithelial cells (e.g. skin or mucus cells).

Attachment: In this process, the replication cycle begins with the adsorption of the virus to its cellular receptors, a heparan sulfate. The gene encoding this protein, the HS3ST6 gene (HS3ST6 stands for "heparan sulfate glucosamine 3-sulfotransferase 6") encodes the 3'-phospho-5'-adenylyl sulfate (PAPS) which catalyzes the transfer of a sulfo group to heparan sulfate. Substrate-specific O-sulfation converts non-anticoagulant heparan sulfate to anticoagulant heparan sulfate. This produces an enzyme-modified heparan sulfate that acts as a binding receptor for herpes simplex virus-1 (HSV-1), allowing its entry. Subsequently, specific interactions occur with protein receptors on the cell surface.

The viral envelope adsorbs to receptors on the plasma membrane of the host cell. Here, the attachment is heparan sulfates or modified heparan sulfates (Hof H et al. 2019) to which the virus can bind with its glycoproteins from the gB family. Subsequently, specific interactions with protein receptors on the cell surface occur. These include integrins (integrin ITGAV:ITGB6 acts as a receptor for for herpes simplex virus-1/HHV-1 (Gianni Tet al. 2013). and glycoproteins from the gD, gH and gL families as well as MHC molecules. This is followed by the fusion of the viral envelope with the cell membrane. The DNA-containing capsid is released into the cytoplasm. It is likely that the capsid can interact with the microtubular transport system of the cell, resulting in transport to the nuclear membrane of the cell. There, the genomic DNA-protein complex can be translocated into the nucleus via a nuclear pore. Here, the linear viral genome is circularized and is now episomally present in the nucleus. Subsequent replication proceeds in a stepwise manner.

Replication: First, the viral DNA is transcribed in the nucleus. Messenger RNAs generated from the transcripts are translated in the cytoplasm. The first translation steps involve the so-called "intermediate early" (IE) proteins. The IE proteins consist mainly of regulatory proteins that are necessary for the subsequent transcription processes ("early" E proteins). Among these E-proteins there is also a DNA polymerase which is responsible for the replication of the DNA genome. After the start of DNA replication, transcription of the "Late"-L genes also begins, among which are mainly the structural proteins of the virus.

Maturation and egress: The assembly of the capsid, including the packaging of the linear viral genome, takes place in the nucleus. The ability to infect cells is acquired when the capsids are enveloped by budding through the inner lamella of the nuclear membrane and in some cases by other membranes of the cell. Viral particles accumulate in the space between the inner and outer lamellae of the nuclear membrane and in the endoplasmic reticulum. The viral particles are transported to the cell surface by the cell's vesicular transport system, where they leave the host cell after fusion of the transport vesicles with the cell membrane.

Viral latency: Before the immune system has brought the infection under control, the viruses also infect certain neurons. In the nucleus of these neurons, the viral DNA is deposited alongside the neuronal DNA as episomal DNA (the viral DNA attached to the nucleus closes to form a ring). In this form, the virus then behaves silently and cannot be detected by the immune system (latent infection). Due to certain influences (e.g. immunosuppression, stress (e.g. disgust), illness, hormonal fluctuations, UV radiation), the virus becomes active again, destroys the nerve cell and then attacks epithelial cells again, so that an acute herpes disease occurs.

Human pathogenic (affecting humans) human herpes viruses (HHV) are divided into 8 groups. The individual species are each triggers for specific diseases. Typical for herpes viruses is their ability to persist in the target cells of the host for life. In the case of immune disorders, this can lead to later reactivation.

Alphaherpesvirinae

• HHV-1: Simplex virus: Herpes simplex type 1 (HHV-1): Herpes simplex, herpes simplex labialis, herpes simplex genitalis, stomatitis aphtosa (see herpes simplex virus infections below). HHV-2: Herpes simplex type 2 (HHV-2): Herpes simplex, genital herpes simplex.
• Herpes B (herpesvirus siniae/monkey herpes)
• HHV-3: Varicella virus (VZV): Chickenpox, congenital varicella syndrome, shingles (herpes zoster).

Betaherpesvirinae

• HHV-5: Cytomegalovirus (CMV): CMV pneumonia, CMV sialoadenitis, CMV colitis, etc.
• HHV-6: Human herpesvirus 6: Exanthema subitum (so-called three-day fever); basal cell carcinomas, squamous cell carcinomas (HHV-6 as possible cofactors); apparently there is a connection between the reactivation of HHV-6 and the severity of drug-induced DRESS syndrome(drug reaction with eosinophilia and systemic symptoms). Initial infection with HHV-6 in 95% of cases before the age of 2. In adults, the primary infection is accompanied by a highly febrile clinical picture with maculo-papular exanthema, lymphadenopathy and possible complications of hepatitis and meningoencephalitis.
• HHV-7: Roseolovirus: Human herpesvirus 7): Pityriasis rosea (?), lichen planus (?), occasionally the virus could be detected in an exanthema subitum.

Gammaherpesvirinae

• HHV-4/Lymphocryptovirus: Epstein-Barr virus (EBV): Mononucleosis, infectious (Pfeiffer's glandular fever), nasopharyngeal carcinoma, Hodgkin's disease: suspected cofactor, but not proven, non-Hodgkin's lymphomas (including Burkitt's lymphoma), post-transplant lymphoproliferation.

• HHV-8/Rhadinovirus: Human herpes virus-8: Kaposi's sarcoma, pemphigus vulgaris, various lymphomas, mycosis fungoides, parapsoriasis en plaques.

Antiviral therapies of herpes diseases inhibit the viral DNA polymerase and thus the reproduction of the virus. Aciclovir a guanosine analogue is taken up by infected cells and converted into the active viral form by a virus-encoded thymidine kinase. Aciclovir inhibits viral DNA synthesis by competing with deoxyguanosine triphosphate. The consequence is a break in the DNA chain. No functional genome can be produced.

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