**2.2 Pathogenesis**

*Human Herpesvirus Infection - Biological Features, Transmission, Symptoms, Diagnosis...*

chickenpox and Herpes Zoster (HZ), both belong to αHV.

**2.1 Clinical aspects of αHV lesions**

Betaherpesvirinae, and Gammaherpesvirinae); among these, only the αHV creates skin lesions in humans [2]. The Herpes Simplex Virus (HSV), creating the general clinical picture of herpetic disease, and the Varicella-Zoster Virus (VZV), which is the cause of

The transmission of αHV occurs by close contact with a person who actively eliminates the virus. The viral diffusion occurs from lesions; however, it can occur even if they are not visible. After the primary infection, the αHV remains quiescent in the nerve ganglia from which it can periodically reactivate, causing clinical manifestations. The HSV commonly cause a relapsing mucocutaneous infection affecting the skin, mouth, lips, eyes and genitals. Serious common variants include encephalitis, meningitis, neonatal herpes, and infections disseminated in immunosuppressed patients. There are two types of HSV: Herpes Simplex Virus 1 (HSV-1) and Herpes Simplex Virus 2 (HSV-2) and both types can cause oral or genital infections. In most cases, the HSV-1 causes gingivostomatitis, cold sores, herpetic keratitis, and lesions in the upper body. The HSV-2 generally causes lesions to the genitals and to the skin of the lower half of the body. Approximately 70% of population in USA is seropositive for HSV [3] but only the 20%, due to a decline in cellular immunity, presents the recurrent form that can occur with a variable frequency. The mucocutaneous manifestations occur in two forms: primary infection and recurrent infection. Both forms appear on the skin with an erythematous lesion with vesicles (the size of a pin's head) clustered that can merge to form a bubble and then break, leaving an erosion and then a crust that falls after a few days. The primary infection may be unapparent, so that most individuals carry antibodies but have no memory of the initial Herpes. In the forms where the disease manifests itself usually appears in children aged between 6 months and 3 years of age. It presents a clinical presentation often more serious than the classical that is shown in the recurrent form. In fact, it is associated with general malaise with temperature over 39°C, pain, dysphagia, sialorrhea, fetid breath. Despite the impressive appearance it resolves on its own in 10–15 days. During the primary infection the transmission of the virus is favored by alterations of the epithelial lining, so that it penetrates and multiplies in the epithelial cells, with lysis of the infected cells due to the formation of a large number of virions. The virus then disappears from the coating epithelium and goes, passing through the sensory nevi, to localize in the nerve ganglia corresponding to the entry area. In recurrent manifestations usually, after a prodromal period (typically <6 h in HSV-1 relapses) characterized by burning or pruritus, small vesicle bunches appear stretched on an erythematous base. The bunches are 0.5–1.5 cm in size but can flow together. Skin lesions of the nose, ears, eyes, fingers or genitals can be particularly painful. The vesicles normally persist for a few days, then break and dry, forming a thin yellowish crust. The lesions can be associated with a burning sensation, tingling or itching with or without fever and small adenopathies, the evolution lasts 1–2 weeks. The herpetic lesions typically heal completely, but recurrent lesions in the same site can cause atrophy and scarring. Skin lesions can develop bacterial superinfections. In patients with depression of cell-mediated immunity due to Human Immunodeficiency Virus infection (HIV) or other causes, long-lasting or progressive lesions may persist for weeks or longer. Herpes labialis (HL) occurs on the edge of the vermilion of the lip or, less frequently, on the mucosa of the hard palate. HL is the most common clinical form in the facial region [4]. In the United Kingdom it accounts for 1% of medical consultations [5]. The acute gingivostomatitis is characteristic of childhood. Instead, herpetic pharyngitides can occur in adults and children; occasionally, mediated by oro-genital contacts, caused by the HSV-2. The intraoral and gingival

**12**

HSV infections are most commonly acquired through direct contact with mucosal tissue or secretions of another infected person and the majority of infections are established within the stratified squamous epithelium of the skin and oral or genital mucosa [10]. The virus is able to cause a lytic infection with direct death of epithelial cells. Following infection, the virus enters sensory nerves that innervate the skin or mucosa and travels via retrograde axonal transport to the neuronal cell body: here it can establish a life-long latent infection in dorsal root ganglia [11]. In the cell body there is the nucleus, where the virus makes use of the cell's apparatus for DNA replication and transcription. The axonal cytoskeleton and molecular motors, like kinesins, are involved in the active transport of viral capsids and glycoproteins: their transport seems to be fast, bidirectional and microtubules dependent [12–14]. The mechanisms that regulate entry into lytic replication versus latent infection in neurons remain largely undefined. The mechanism of HSV entry is mediated by direct interaction between viral envelope glycoproteins and cell surface receptors that mediate attachment, initiate signaling cascades, or trigger virus internalization.

The entry process involves multiple steps:


delivery of the viral nucleocapsid to the cytoplasm accomplished either by membrane fusion or endocytosis/phagocytosis-like uptake. Beside membrane fusion, mechanisms of endocytosis and/or a phagocytosis-like uptake have been proposed. The endocytosis of HSV particles is atypical, because not mediated by clathrin-coated pits or caveolae. The phagocytosis process requires a cytoskeletal rearrangement with activation of Rho GTPases [18].

After fusion between the cellular membrane with the infecting virus, a viral transactivator tegument protein (VP16), is released into the cytoplasm. The viral capsid is then transported to the nuclear membrane along the microtubule network and, through nuclear pore, the viral DNA is released into the nucleus. VP16 forms a transactivation complex binding in the cytoplasm host cell factor-1 (HCF-1) (protein that contains a nuclear localization sequence), and in the nucleus the homeodomain protein Octamer binding protein-1 (Oct-1). These proteins form a trimeric complex able to activate the immediate early (IE) gene expression [19]. Successful lytic replication is dependent on the expression of the viral IE genes within all infected cells. While this model of VP16 activation of IE gene expression is well understood, the mechanisms implicated in neuronal latency are debated and considerable gaps remain in our knowledge of how different signaling pathways act on the latent genome for reactivation. Following the establishment of latent infection, viral lytic gene expression is silenced, and the lytic gene promoters are associated with repressive heterochromatin [20]. Key experiments performed in the 1980s indicated that latent genomes in the brain stems of infected mice have a nucleosomal structure [21]. Later studies confirmed that the latent viral genome associates with cellular histones in the trigeminal ganglia of mice [22, 23]. Coinciding with the silencing of lytic transcripts, the viral lytic gene promoters become enriched with characteristic heterochromatic histone modifications [24, 25]. While it appears that factors intrinsic to neurons play a key role in the transcriptional silencing of the virus, viral gene products expressed during latent infection can also modulate the chromatin structure [23, 26, 27]. This modulation likely promotes long-term latency, while priming the genome for reactivation following the appropriate stimuli [28, 29].
