**4.2 The pathogen**

Herpes simplex is a large DNA virus (150–200 nm) from the genus Simplex virus, subfamily Alphaherpesvirinae, and family Herpesviridae. It is a neurotropic virus with an envelope and depending on the protein coat, it can be named HSV-1 or HSV-2. HSV-2 shares>80% identity on the amino acid level with HSV-1. Both types can infect the oral or genital skin or mucosa and cause recurrent ulcerations.

#### **Figure 2.**

*Comparison between HSV-1 and HSV-2 in terms of age of onset, most affected gender, infectivity, transmission, prevalence, and incidence.*

#### **Figure 3.**

*Comparison between HSV-1 and HSV-2 based on the first episode, latency site, viral shedding, and subsequent recurrences.*

The HSV genome consists of two covalently linked components, designated as L (long) and S (short). Each component is formed by unique sequences (UL and US, respectively) flanked by regions of repeated and inverted sequences that facilitate replication of the genome. The DNA molecular weight is estimated to be approximately 150 kbp, with a G + C content of 68% for HSV-1 and 69% for HSV-2. The viral composition is important for generating an immunogenic response, some of the most important proteins are in the capsid including VP5, VP19C, VP23, VP24, VP26, and the protein encoded by the UL6 gene. Another important component of the virion is the envelope, which consists of a lipid bilayer with approximately 11 viral glycoproteins, four of which (gB, gD, gH, and gL) are essential for virus entry into cells.

#### **4.3 The disease**

Once the virus replicates in the host, the intact virion is transported through a retrograde axonal flow to the sensory or autonomic ganglia, where the virus can remain in a latent form in the trigeminal ganglia for HSV-1 and the dorsosacral roots for HSV-2. Recurrences can occur when the latent virus is reactivated, being carried by anterograde axonal flow to the region of the primary infection. This reactivation is triggered by local stimuli (i.e., injury to the innervated tissue harboring latent HSV, systemic factors as physical or emotional stress, fever, exposure to ultraviolet light, menstruation, and hormonal imbalance).

Genital herpes is presented with one or more vesicles, or small blisters, on or around the genitals, rectum, or mouth. The average incubation period for an initial herpes infection is 4 days, ranging from 2 to 12 days after exposure. The vesicles then break leaving painful ulcers that may take 2–4 weeks to heal after the initial herpes infection; this is known as "outbreak" or genital herpes episode.

There are differences between the first and recurrent outbreaks. The first outbreaks have a longer duration of herpetic lesions, the viral shedding is increased (this makes HSV transmission more likely) and the patients experience more systemic symptoms like fever, body aches, swollen lymph nodes, or headache. In the case of the recurrent outbreaks, the duration is shorter and these episodes are less severe than the first outbreak; recurrent outbreaks are very common and normally have prodromal symptoms, either localized genital pain or tingling or shooting pains in the legs, hips, or buttocks, which occur hours to days before the eruption of herpetic lesions. The number of symptomatic recurrent outbreaks may decrease over time.

It is important to highlight that recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than for genital HSV-2 infection.

Another important clinical manifestation in children and adolescents is HSV encephalitis, this can occur because of a primary or recurrent HSV-1 infection. The most common sign and symptoms include fever, alterations in the state of consciousness, personality changes, seizures, and other neurological symptoms. A form of self-limited aseptic meningitis has been associated with genital HSV-2 infection. HSV can cause other unusual central nervous system manifestations such as Bell's palsy, ascending and transverse myelitis, postinfectious encephalomyelitis, and recurrent meningitis.

#### **4.4 Treatment**

Currently, there is no treatment able to definitively cure genital herpes; some antiviral chemotherapy offers control and relief to the most symptomatic patients; also, recurrences can be reduced but not eradicated. For these patients, Acyclovir

*Sexually Transmitted Infections in Pediatrics DOI: http://dx.doi.org/10.5772/intechopen.101674*

can be used for initial episodes, in the case of recurrences, 45, 52 and 63% of patients remain free of recurrences in the first, second and third year of treatment. Valacyclovir is also used for the initial episode and as suppressive therapy, it has been considered as the gold standard therapy; after 6 months of using valacyclovir almost 55% of the patients remain without recurrences and 34% one year after.

For a first episode, oral acyclovir is recommended 400 mg three times a day for 7–10 days or acyclovir 200 mg five times a day for 7–10 days or valacyclovir 1 g orally twice a day for 7–10 days. For suppressive treatment, valacyclovir can be used 1 g once daily; or acyclovir 400 mg orally twice a day.


A Molecular Mechanism for Abnormal Prion Protein Accumulation

*Keiji Uchiyama and Suehiro Sakaguchi*

## **Abstract**

A fundamental event in the pathogenesis of prion disease is the conversion of cellular prion protein into an abnormally folded isoform (PrPSc), which is the infectious causative agent of disease. With progression of disease, PrPSc is replicated and excessively accumulated in most cases. However, the molecular mechanism for excessive accumulation of PrPSc is not well understood. Recently, Sortilin, a member of the VPS10P domain receptor family, has been identified as a sorting receptor that directs prion protein (PrP) to the lysosomal degradation pathway. Moreover, it has been shown that prion infection impairs Sortilin function, resulting in delayed PrPSc degradation. In this chapter, we explain the mechanisms for PrP trafficking into the lysosomal degradation pathway mediated by Sortilin and overaccumulation of PrPSc caused by Sortilin dysfunction.

**Keywords:** PrPSc, PrPSc accumulation, PrPSc degradation, Sortilin, sorting, VPS10P domain, sorting receptor, VPS10P domain receptor

### **1. Introduction**

Prion diseases are a group of fatal neurodegenerative disorders that are caused by the transmissible misfolded isoform (PrPSc) of the cellular prion (PrPC) [1], including Creutzfeldt-Jakob disease of humans, bovine spongiform encephalopathy, and scrapie of sheep. PrPSc is a β-sheet rich conformer of PrPC and is partially resistant to protease. With progression of prion disease, PrPSc is replicated and accumulated in the brain, and neuronal dysfunction and death occur. Previous studies have shown that PrP-null mice neither develop the disease nor accumulate PrPSc even after prions are inoculated into their brains [2, 3]. This indicates that replication and accumulation of PrPSc are closely related to the pathogenesis of prion disease. Therefore, elucidation of the mechanisms of PrPSc degradation and accumulation is critical for understanding the pathogenic mechanism of prion disease and for developing therapeutic agents.

PrPSc usually accumulates excessively over PrPC in cultured cells and mouse brains (**Figure 1**). This strongly indicates that PrPSc is protected against its proteolytic degradation. Actually, several studies have reported that the proteolytic systems (e.g., lysosomal degradation and ubiquitin-proteasomal degradation systems) are inhibited by prion infection [4–7], and PrPSc is found at the cell surface and in endosomal/lysosomal compartments [8–10]. Moreover, when PrPSc was

#### **Figure 1.**

*PrP expression in mice brain and N2a cells. (A) Total PrP and PrPSc were compared between RML prion infected mouse brains at terminal stage and age matched uninfected mice brain by western blotting. (B) N2a cells were treated with uninfected or 22 L-prion infected mice brain homogenate. At 30 dpi, total PrP and PrPSc were detected by western blotting. Blots were probed with anti-PrP antibody (6D11) and anti-*β*-actin antibody.*

fractionated by detergent-based biochemical fractionation, most of the PrPSc was detected in detergent-resistant membrane (DRM) fractions [11], suggesting that PrPSc mainly exists in membrane bound form and PrPSc is degraded preferentially in lysosomes, but not by cytosolic proteasomes. PrPSc to be degraded in lysosomes might be preferentially selected and directed into the lysosomal degradation pathway by dedicated membrane trafficking machinery. Therefore, knowledge of the mechanism that sorts PrP into late endosomal/lysosomal compartments should be important for understanding the accumulation of PrPSc.