**4. The Sun radiation and interaction whit skin**

The skin is continually subjected to the action of external agents including solar radiation. One of the scientifically documented triggers for herpes outbreaks is the ultraviolet (UV) light found in direct sunlight.

### **4.1 The Sun as origin of the electromagnetic energy**

The Sun is a G-type main-sequence star and is the largest and the most massive object in the solar system. The Sun is the source of the overwhelming majority of light, heat, and energy on Earth's surface, and is powered by nuclear fusion of hydrogen nuclei into helium. As a result of these nuclear reactions a continuous flow of particles and electromagnetic waves called the solar wind is released in the cosmos. Solar wind is a constant stream of plasma and particles emanating from the sun and is the extension of solar corona into interplanetary space. The solar wind invests all the planets, can reach speeds above 700 km/s and have a density that varies from 10 to 100 particles/cm3 . Sunlight consists mostly of short wavelength ionizing radiation (cosmic, gamma, and X-rays) and long wavelength non-ionizing radiation (UV, visible, and infrared) [48].

UVR is the area of the electromagnetic spectrum that is considered biologically the most active and therefore of greatest impact on health and disease [49]. For convenience, we separate UV somewhat arbitrarily into UVA (315–400 nm), UVB (280–315 nm) and UVC (100–280 nm). UVC together with ionizing radiation is largely absorbed by the upper atmosphere and does not reach us on the earth's surface. Most UVR that reaches the earth's surface is UVA (95%), only a small percentage is UVB (approximately 5%). UVR peaks around noon and is increased by reflection from snow, water, and sand [50]. UVA, but not UVB, can penetrate glass [51]. The solar radiation is omnipresent during daylight hours. At ground level the amount of UV mainly comprises UVA, and a small percentage (<10%, variable by time of day, season and altitude) of UVB. The doses of UV absorbed vary greatly within a person and between people, depending on the position, time of day, season, type of clothing, habits and skin pigmentation.

The non-ionizing radiation are not lethal to living organisms but can cause damage to the skin and eyes if taken chronically and/or in large quantities. Animals defend themselves from the action of these waves thanks to the presence on their skin of hairs, feathers and scales. Humans, having lost the hair during evolution, have to use melanin as a means of protection. The peculiarity of the UV is that they are one of the few environmental factors that can cause both disease and protection against the disease [52]. The sun exposure is pleasant for us because it causes the following positive effects: we are pervaded by a pleasant feeling of warmth and well-being linked to Infrared Radiation (IR) and Visible Light (VL), we release chemical factors that act as antidepressants (VL), appears after a few hours a dark and transient tanning (UVA), followed by a golden and lasting tan (UVB) after 24–48 h. Other positive actions are the production of "antirachitic" vitamin D (UVB) and a regulation of hormonal functions (VL). Unsuitable exposure can lead to immediate or delayed side effects. The most frequent damages caused by sunlight are: sunburn, photoallergic reactions, photo-aging, skin tumors, eye diseases and immunosuppression.

### **4.2 UVR and immune skin suppression**

Exposure to UVR has a profound effect on the skin immune system. It has both, pro-inflammatory as well as immunosuppressive effects and it involves both innate and adaptive immunity. Examples of pro-inflammatory responses clinically observed include sunburn, photodermatosis [53]. Examples of the immunosuppressive effect is the use of UV for psoriasis or lichen planus treatment. Both UVB and UVA wavebands contribute to sunlight-induced immunosuppression, although an interaction between them makes sunlight more suppressive than each waveband alone. It is therefore important to protect the skin from both UVB and UVA. Exposure to doses of UVR that are only 30–50% as high as what is required to cause barely detectable sunburn, suppressing immunity in humans. Therefore, normal daily outdoor activities during spring and summer months are likely to cause some degree of immunosuppression in a large proportion of humans [54]. It is both obvious and striking that UVR at rather low doses suppresses an immune response. Thus, one may speculate that a certain degree of immunosuppression may be beneficial. The skin is an organ which is constantly exposed to potential allergens; in addition, the skin is an organ which is prone to autoimmunity [55, 56]. Hence, it is tempting to speculate that a certain degree of constant immunosuppression by daily solar exposure may prevent the induction of these immune responses. Owing to the multiple different experimental systems suppressed by UV and the dependence on dose, timing, waveband and skin site, we currently do not have a comprehensive understanding of how UV has this potent effect on the immune system. However, many different molecular and cellular events have been described. The cells involved in immunosuppressive activity are

**17**

**Figure 1.**

*in the skin after the ultraviolet radiation exposure.*

*Sunlight and Herpes Virus*

*DOI: http://dx.doi.org/10.5772/intechopen.82643*

keratinocytes, lymphocytes, Langerhans cells (LC), macrophages and mast cells. UVR induced immune suppression is known be mediated through T cells [57]. The relation of immune suppression is linked to various subtypes of regulatory immune cells such as regulatory T cells (Tregs) and regulatory B cells (Bregs) depends on UVR doses and type of immune response [58–61]. Furthermore, UVR has also profound effects on antigen-presenting cells. It damages LCs, so that they migrate from epidermis into the draining lymph nodes [62, 63]. It affects mast cells which are known to be involved in immune suppression [64]. It releases cytokines leading suppressor macrophages to infiltrate the skin and activating B lymphocytes in draining lymph nodes so that they have suppressor function. It is likely that interaction between these UV-altered antigen-presenting cells result in the activation of suppressor T lymphocytes. There is good evidence that these T suppressor cells are mainly responsible for reduction in immunity caused by UV [54]. The molecular mechanisms responsible for disruption of cellular immunity and some of the key events observed in the skin after the UVR exposure are described below (**Figure 1**). The cellular-molecular phenomena occur in successive steps. In the first step, which concerns keratinocytes, LC, urocanic acid (UCA) and corneum lipids, some ray-sensitive photoreceptors absorb photons, with different susceptibility for the different wavelengths (so the results can be different depending on the type of UV) and initiate a molecular cascade that damages and modifies the cellular biochemistry. The molecular mechanisms responsible for disruption of cellular immunity begins with DNA damage, trans to cis isomerization of UCA, and peroxidation of lipids. In the second step, the cells damaged by UVR produce mediators (especially cytokines) that modify the activity of LC. In fact, both for the cytokines and for their own damaged DNA, in addition to the alteration of the antigen presentation, they migrate into the lymph nodes. The cytokines produced in this phase are numerous. It has also been observed that UVR suppresses HSV antigen presentation in epidermal cells and leads to the reduction of type 1 cytokine release, an important key-factor in immunological control for viruses such as HSV [65, 66]. Photoproducts of DNA such as pyrimidine dimers or 6-4-photoproducts result in the production and release of various immunosuppressive factors such as Tumor Necrosis Factor (TNF)-alpha and

*The molecular mechanisms responsible for disruption of cellular immunity and some of the key events observed* 

#### *Sunlight and Herpes Virus DOI: http://dx.doi.org/10.5772/intechopen.82643*

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

season, type of clothing, habits and skin pigmentation.

**4.2 UVR and immune skin suppression**

UVR is the area of the electromagnetic spectrum that is considered biologically the most active and therefore of greatest impact on health and disease [49]. For convenience, we separate UV somewhat arbitrarily into UVA (315–400 nm), UVB (280–315 nm) and UVC (100–280 nm). UVC together with ionizing radiation is largely absorbed by the upper atmosphere and does not reach us on the earth's surface. Most UVR that reaches the earth's surface is UVA (95%), only a small percentage is UVB (approximately 5%). UVR peaks around noon and is increased by reflection from snow, water, and sand [50]. UVA, but not UVB, can penetrate glass [51]. The solar radiation is omnipresent during daylight hours. At ground level the amount of UV mainly comprises UVA, and a small percentage (<10%, variable by time of day, season and altitude) of UVB. The doses of UV absorbed vary greatly within a person and between people, depending on the position, time of day,

The non-ionizing radiation are not lethal to living organisms but can cause damage to the skin and eyes if taken chronically and/or in large quantities. Animals defend themselves from the action of these waves thanks to the presence on their skin of hairs, feathers and scales. Humans, having lost the hair during evolution, have to use melanin as a means of protection. The peculiarity of the UV is that they are one of the few environmental factors that can cause both disease and protection against the disease [52]. The sun exposure is pleasant for us because it causes the following positive effects: we are pervaded by a pleasant feeling of warmth and well-being linked to Infrared Radiation (IR) and Visible Light (VL), we release chemical factors that act as antidepressants (VL), appears after a few hours a dark and transient tanning (UVA), followed by a golden and lasting tan (UVB) after 24–48 h. Other positive actions are the production of "antirachitic" vitamin D (UVB) and a regulation of hormonal functions (VL). Unsuitable exposure can lead to immediate or delayed side effects. The most frequent damages caused by sunlight are: sunburn, photoallergic

reactions, photo-aging, skin tumors, eye diseases and immunosuppression.

Exposure to UVR has a profound effect on the skin immune system. It has both, pro-inflammatory as well as immunosuppressive effects and it involves both innate and adaptive immunity. Examples of pro-inflammatory responses clinically observed include sunburn, photodermatosis [53]. Examples of the immunosuppressive effect is the use of UV for psoriasis or lichen planus treatment. Both UVB and UVA wavebands contribute to sunlight-induced immunosuppression, although an interaction between them makes sunlight more suppressive than each waveband alone. It is therefore important to protect the skin from both UVB and UVA. Exposure to doses of UVR that are only 30–50% as high as what is required to cause barely detectable sunburn, suppressing immunity in humans. Therefore, normal daily outdoor activities during spring and summer months are likely to cause some degree of immunosuppression in a large proportion of humans [54]. It is both obvious and striking that UVR at rather low doses suppresses an immune response. Thus, one may speculate that a certain degree of immunosuppression may be beneficial. The skin is an organ which is constantly exposed to potential allergens; in addition, the skin is an organ which is prone to autoimmunity [55, 56]. Hence, it is tempting to speculate that a certain degree of constant immunosuppression by daily solar exposure may prevent the induction of these immune responses. Owing to the multiple different experimental systems suppressed by UV and the dependence on dose, timing, waveband and skin site, we currently do not have a comprehensive understanding of how UV has this potent effect on the immune system. However, many different molecular and cellular events have been described. The cells involved in immunosuppressive activity are

**16**

keratinocytes, lymphocytes, Langerhans cells (LC), macrophages and mast cells. UVR induced immune suppression is known be mediated through T cells [57]. The relation of immune suppression is linked to various subtypes of regulatory immune cells such as regulatory T cells (Tregs) and regulatory B cells (Bregs) depends on UVR doses and type of immune response [58–61]. Furthermore, UVR has also profound effects on antigen-presenting cells. It damages LCs, so that they migrate from epidermis into the draining lymph nodes [62, 63]. It affects mast cells which are known to be involved in immune suppression [64]. It releases cytokines leading suppressor macrophages to infiltrate the skin and activating B lymphocytes in draining lymph nodes so that they have suppressor function. It is likely that interaction between these UV-altered antigen-presenting cells result in the activation of suppressor T lymphocytes. There is good evidence that these T suppressor cells are mainly responsible for reduction in immunity caused by UV [54]. The molecular mechanisms responsible for disruption of cellular immunity and some of the key events observed in the skin after the UVR exposure are described below (**Figure 1**). The cellular-molecular phenomena occur in successive steps. In the first step, which concerns keratinocytes, LC, urocanic acid (UCA) and corneum lipids, some ray-sensitive photoreceptors absorb photons, with different susceptibility for the different wavelengths (so the results can be different depending on the type of UV) and initiate a molecular cascade that damages and modifies the cellular biochemistry. The molecular mechanisms responsible for disruption of cellular immunity begins with DNA damage, trans to cis isomerization of UCA, and peroxidation of lipids. In the second step, the cells damaged by UVR produce mediators (especially cytokines) that modify the activity of LC. In fact, both for the cytokines and for their own damaged DNA, in addition to the alteration of the antigen presentation, they migrate into the lymph nodes. The cytokines produced in this phase are numerous. It has also been observed that UVR suppresses HSV antigen presentation in epidermal cells and leads to the reduction of type 1 cytokine release, an important key-factor in immunological control for viruses such as HSV [65, 66]. Photoproducts of DNA such as pyrimidine dimers or 6-4-photoproducts result in the production and release of various immunosuppressive factors such as Tumor Necrosis Factor (TNF)-alpha and

#### **Figure 1.**

*The molecular mechanisms responsible for disruption of cellular immunity and some of the key events observed in the skin after the ultraviolet radiation exposure.*

interleukin (IL)-10 by keratinocytes and other cells in the skin. The UVB waveband in particular also directly leads to isomerization of trans-UCA to cis-UCA. Cis-UCA induces immune suppression by binding to the 5-HT2A receptor, leading in turn to production of IL-10 by T-cells and B-cells. It may also indirectly lead to mast cell degranulation and stimulate the release of Platelet-Activating Factor (PAF). Formation of reactive oxygen species (ROS) by UVR not only induces and contributes to DNA damage but also directly stimulates PAF synthesis or the production of PAF-like molecules. UVR can also directly upregulate specific antimicrobial peptides (AMP) such as human beta-defensin-2, beta-defensin-3, S100A7, and RNase7 which are expressed by keratinocytes, lymphocytes, monocytes, and mast cells. These AMPs not only serve as initiators of innate immune response but they also communicate with the adaptive immune system and can activate it. The third step, as a result of the impact of UVR on the skin, is the appearance of an immunosuppressive microenvironment with abundance of TNF, IL-4 and IL-10 linked to Langerhans cell (LC) migration into lymph nodes and neutrophil and macrophage recruitment to the skin. As overall result, there is a modulation on T lymphocytes characterized by a global suppression of them and by a switch in the balance between two lymphocytes classes: the suppression of the Th1 population (implicated in immunity to intracellular organisms like viruses, through IL-2 and INF); an increase of Th2 (implicated in immunity against extracellular microbes such as bacteria, through IL-4/10) and an induction of Tregs and Bregs leading ultimately to functional immune suppression [67, 68].

### **4.3 Is UVR a cause of αHV recurrence?**

A systematic epidemiological review was carried out in 2008 identifying 9 diseases that show sufficient evidence of a causal relationship with UVR exposure. These include the reactivation of the HSV. The other diseases are: melanoma, squamous cell carcinoma of the skin, basal cell carcinoma, solar keratoses, sunburns, cataracts, pterygium, squamous cell carcinoma of the cornea and conjunctiva [52]. In medical scientific literature several works have been published demonstrating the recurrence of αHV after exposition to solar UVR (sUVR) or experimental UVR (eUVR) both on human [69–74] and on animal models; [75, 76] due to these reasons most dermatology manuals recommend using sunscreen to avoid HSV recurrence [77]. Several papers have shown a correlation between UV exposure and occurrence of HSV-1 [74, 78]. Approximately the 25–50% of HL are attributed, at least in part, to sUVR exposure. In one scientific article it was shown that the use of sunscreen alone versus placebo showed 95–100% suppression of HL recurrences in 2 crossover trials after application of 4 Minimal Erythema Doses (MED) of eUVR [70, 79]. To evaluate the role of exposure to sUVR in primary and recurrent HSV-1 infections, the selfreported cause of infection among diagnosed patients in Hyogo Prefecture, Japan, was investigated. Among 4295 infected patients, 3678 had HSV-1, and 2656 of those patients (72.2%) had a recurrent flare-up. Sun-induced HSV-1 flare-up was reported by 10.4% of the total study population. However, this increased to 19.7% among patients diagnosed in July and August, to 28% among patients younger than 30 years diagnosed in July and August, and to 40% among patients younger than 30 years diagnosed in July and August with a recurrent infection [32]. Although these studies did not analyze HG, data from another study show that HG recurrences also occur more easily after exposure to UV rays. For example, one study found that patients with HG—in this case, on the buttocks—were likely to experience recurrences shortly after being exposed to eURV. Another study on HO compared the reactivation with sUVR, detecting an increase in reactivation in more exposed subjects, actually even if data are unclear due to confounding factors that can be superimposed, such as in particular the stress that might act both directly determining reactivation

**19**

*Sunlight and Herpes Virus*

*DOI: http://dx.doi.org/10.5772/intechopen.82643*

infection developed recrudescences [85].

**4.4 How does solar radiation stimulate viral reactivation?**

The exposure to sunlight has been associated with HSV reactivation [89–91]. It has been observed that 30% of causes of reactivation and axon migration to the skin are due to sudden exposure to sunlight and this seems also linked to the triggering of various mechanisms. There are many ways in which UV exposure is thought to impact αHV, and HSV recurrence in particular, directly through 3 pathways and probably also indirectly with unknown methods [85]. The first pathway is the depression of immune response due to UV exposure. The second pathway by which UVR may affect recurrence is directly through HSV reactivation [80, 85]. The third pathway study molecular events that trigger reactivation. The first pathway is based on the hypothesis that the virus continually tends to migrate from the ganglion to the skin. According to this theory, the normal immune response is activated through cell-mediated mechanisms of lymphocytes and macrophages and through the release of cytokines. In this way most of the migrations of ganglion-to-skin viruses is suppressed, as they are represented by few viral units and because the system is already sensitized, preventing a clinically evident reactivation because the infection remains sub-clinical. In the first pathway, the exposure to UVR determines the imbalance and suppression of the immune system, in a dose-dependent manner, which triggers a series of events so that local control of the reactivation is lost causing some virions to escape from immune control and the disease becomes

and indirectly probably creating a greater need to expose to the sun [80]. As far as the VZV is concerned, one work reported a higher incidence of total HZ cases and cases of zoster in males during summer (from July to September) with a significant increase in May–June in patients studied in 1992–1998 in Ferrara in north-east Italy [81]. Another work shows the incidence of HZ peak for all subjects and for males it coincides with the maximum UVR months in summer. This association was not found for women, considered alone. It has not been explained why this difference should occur between men and women, but one possible explanation could be that older men tend to have more activities outside than women, such as gardening or walking, and therefore more exposure to sUVR. In addition to the increase in the incidence of zoster in summer, there was a significant increase over the same period in cases where lesions occurred on the face were compared to body sites normally covered [8]. In addition to considering the possible influence of the seasons on the incidence of αHV mucocutaneous lesions, some studies have succeeded in demonstrating a correlation with the UVR dose, geographical location, age and the body location. A dose of eUVR capable of triggering the recurrence of HL, is 4 MED, which corresponds to 80 min of sun exposure around 12 in July, at sea level taken by an individual with unprotected fair skin [70]. In some works, a slight latitudinal gradient of HL and a peak of prevalence in adulthood are demonstrated [82–84]. Another work highlighted the photolocalization of viral exanthema by observing a particular distribution of skin lesions, especially for VZV and HSV, between exposed areas and areas covered by clothes, preferring a location exposed to rays [85]. The recurrence time of HL after eVR exposure may be immediate (within 48 h) or delayed (after 2–7 days); [78] the time required for virus reactivation at the latency site [86], virus transport to the skin surface (it is estimated that the speed, demonstrated in vitro, is 3–5 mm/h)] and the virus replication in the epithelium with production of typical lesions (>24 h) [87, 88]. The eUVR had a beneficial effect on the virulence of HSV in an animal model. In fact, in a study it has been shown that 80% of mice irradiated before infection, and then re-irradiated several weeks later, developed recrudescent lesions. Only 20% of equivalent mice had not been irradiated before infection, but when irradiated after

#### *Sunlight and Herpes Virus DOI: http://dx.doi.org/10.5772/intechopen.82643*

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

leading ultimately to functional immune suppression [67, 68].

A systematic epidemiological review was carried out in 2008 identifying 9 diseases that show sufficient evidence of a causal relationship with UVR exposure. These include the reactivation of the HSV. The other diseases are: melanoma, squamous cell carcinoma of the skin, basal cell carcinoma, solar keratoses, sunburns, cataracts, pterygium, squamous cell carcinoma of the cornea and conjunctiva [52]. In medical scientific literature several works have been published demonstrating the recurrence of αHV after exposition to solar UVR (sUVR) or experimental UVR (eUVR) both on human [69–74] and on animal models; [75, 76] due to these reasons most dermatology manuals recommend using sunscreen to avoid HSV recurrence [77]. Several papers have shown a correlation between UV exposure and occurrence of HSV-1 [74, 78]. Approximately the 25–50% of HL are attributed, at least in part, to sUVR exposure. In one scientific article it was shown that the use of sunscreen alone versus placebo showed 95–100% suppression of HL recurrences in 2 crossover trials after application of 4 Minimal Erythema Doses (MED) of eUVR [70, 79]. To evaluate the role of exposure to sUVR in primary and recurrent HSV-1 infections, the selfreported cause of infection among diagnosed patients in Hyogo Prefecture, Japan, was investigated. Among 4295 infected patients, 3678 had HSV-1, and 2656 of those patients (72.2%) had a recurrent flare-up. Sun-induced HSV-1 flare-up was reported by 10.4% of the total study population. However, this increased to 19.7% among patients diagnosed in July and August, to 28% among patients younger than 30 years diagnosed in July and August, and to 40% among patients younger than 30 years diagnosed in July and August with a recurrent infection [32]. Although these studies did not analyze HG, data from another study show that HG recurrences also occur more easily after exposure to UV rays. For example, one study found that patients with HG—in this case, on the buttocks—were likely to experience recurrences shortly after being exposed to eURV. Another study on HO compared the reactivation with sUVR, detecting an increase in reactivation in more exposed subjects, actually even if data are unclear due to confounding factors that can be superimposed, such as in particular the stress that might act both directly determining reactivation

**4.3 Is UVR a cause of αHV recurrence?**

interleukin (IL)-10 by keratinocytes and other cells in the skin. The UVB waveband in particular also directly leads to isomerization of trans-UCA to cis-UCA. Cis-UCA induces immune suppression by binding to the 5-HT2A receptor, leading in turn to production of IL-10 by T-cells and B-cells. It may also indirectly lead to mast cell degranulation and stimulate the release of Platelet-Activating Factor (PAF). Formation of reactive oxygen species (ROS) by UVR not only induces and contributes to DNA damage but also directly stimulates PAF synthesis or the production of PAF-like molecules. UVR can also directly upregulate specific antimicrobial peptides (AMP) such as human beta-defensin-2, beta-defensin-3, S100A7, and RNase7 which are expressed by keratinocytes, lymphocytes, monocytes, and mast cells. These AMPs not only serve as initiators of innate immune response but they also communicate with the adaptive immune system and can activate it. The third step, as a result of the impact of UVR on the skin, is the appearance of an immunosuppressive microenvironment with abundance of TNF, IL-4 and IL-10 linked to Langerhans cell (LC) migration into lymph nodes and neutrophil and macrophage recruitment to the skin. As overall result, there is a modulation on T lymphocytes characterized by a global suppression of them and by a switch in the balance between two lymphocytes classes: the suppression of the Th1 population (implicated in immunity to intracellular organisms like viruses, through IL-2 and INF); an increase of Th2 (implicated in immunity against extracellular microbes such as bacteria, through IL-4/10) and an induction of Tregs and Bregs

**18**

and indirectly probably creating a greater need to expose to the sun [80]. As far as the VZV is concerned, one work reported a higher incidence of total HZ cases and cases of zoster in males during summer (from July to September) with a significant increase in May–June in patients studied in 1992–1998 in Ferrara in north-east Italy [81]. Another work shows the incidence of HZ peak for all subjects and for males it coincides with the maximum UVR months in summer. This association was not found for women, considered alone. It has not been explained why this difference should occur between men and women, but one possible explanation could be that older men tend to have more activities outside than women, such as gardening or walking, and therefore more exposure to sUVR. In addition to the increase in the incidence of zoster in summer, there was a significant increase over the same period in cases where lesions occurred on the face were compared to body sites normally covered [8]. In addition to considering the possible influence of the seasons on the incidence of αHV mucocutaneous lesions, some studies have succeeded in demonstrating a correlation with the UVR dose, geographical location, age and the body location. A dose of eUVR capable of triggering the recurrence of HL, is 4 MED, which corresponds to 80 min of sun exposure around 12 in July, at sea level taken by an individual with unprotected fair skin [70]. In some works, a slight latitudinal gradient of HL and a peak of prevalence in adulthood are demonstrated [82–84]. Another work highlighted the photolocalization of viral exanthema by observing a particular distribution of skin lesions, especially for VZV and HSV, between exposed areas and areas covered by clothes, preferring a location exposed to rays [85]. The recurrence time of HL after eVR exposure may be immediate (within 48 h) or delayed (after 2–7 days); [78] the time required for virus reactivation at the latency site [86], virus transport to the skin surface (it is estimated that the speed, demonstrated in vitro, is 3–5 mm/h)] and the virus replication in the epithelium with production of typical lesions (>24 h) [87, 88]. The eUVR had a beneficial effect on the virulence of HSV in an animal model. In fact, in a study it has been shown that 80% of mice irradiated before infection, and then re-irradiated several weeks later, developed recrudescent lesions. Only 20% of equivalent mice had not been irradiated before infection, but when irradiated after infection developed recrudescences [85].

## **4.4 How does solar radiation stimulate viral reactivation?**

The exposure to sunlight has been associated with HSV reactivation [89–91]. It has been observed that 30% of causes of reactivation and axon migration to the skin are due to sudden exposure to sunlight and this seems also linked to the triggering of various mechanisms. There are many ways in which UV exposure is thought to impact αHV, and HSV recurrence in particular, directly through 3 pathways and probably also indirectly with unknown methods [85]. The first pathway is the depression of immune response due to UV exposure. The second pathway by which UVR may affect recurrence is directly through HSV reactivation [80, 85]. The third pathway study molecular events that trigger reactivation. The first pathway is based on the hypothesis that the virus continually tends to migrate from the ganglion to the skin. According to this theory, the normal immune response is activated through cell-mediated mechanisms of lymphocytes and macrophages and through the release of cytokines. In this way most of the migrations of ganglion-to-skin viruses is suppressed, as they are represented by few viral units and because the system is already sensitized, preventing a clinically evident reactivation because the infection remains sub-clinical. In the first pathway, the exposure to UVR determines the imbalance and suppression of the immune system, in a dose-dependent manner, which triggers a series of events so that local control of the reactivation is lost causing some virions to escape from immune control and the disease becomes

manifest. It does not seem that through this mechanism we can identify a "remote" influence that reactivates the virus, but only a local effect of more peripheral virions approaching the skin. In the second pathway, UVR directly determine an imbalance or radiation damage to epidermal and dermal cells, which are stimulated to repair producing transcription factors that in addition to activating cellular gene expression also activate the viral one and also inhibit the stimulus to apoptosis [80]. Especially the cell repair, through the c-Jun and c-Fos transcription factors, activates the HSV transcription promoter (infected cell polypeptide 0), leading to HSV transcription and reactivation [92]. Additionally, these repair pathways circumvent the activity of HSV latency-associated transcript preventing infected neurons from undergoing apoptosis and in turn, reactivating HSV [93]. Despite these models, significant gaps remain in our understanding of how these stimuli correlate with reactivation of the virus resulting in clinical disease. The third pathway is a molecular model that explains how UVR at the body surface results in multiple neuronal effects or hormonal alteration that could be relevant to reactivation. For example, a damage to innervated tissues that results in loss of the neurotrophin-producing cells and changes in the levels of regulatory neuropeptides, neurotrophins, neurotransmitters may occur following UV irradiation [94]. Nerve growth factor (NGF) deprivation was first found to trigger HSV reactivation in primary neuronal models of HSV latency using rat sympathetic neurons [95]. In vivo injection of anti-NGF serum into latently infected rabbits has also been shown to enhance reactivation of HSV [96]. Furthermore, interruption of signals downstream of the NGF receptor triggered reactivation in a variety of in vitro models of HSV latency [97–100], and has been shown to enhance explant mediated reactivation ex vivo [101, 102]. In addition, UV treatment in mice results in increased serum levels of cortisol and may act through a pathway that is similar to psychological stress-induced reactivation. It was also noted that the dexamethasone, a synthetic corticosteroid, stimulates reactivation of HSV-1 both ex vivo and in primary neuronal cultures, and the closely related bovine HSV-1 can also be reactivated in latently infected calves by intravenous injection of dexamethasone [98, 101, 103].

#### **4.5 Do sun-screen reduce HSV recurrence?**

To date four studies have been published on sunscreen used by volunteers who suffered from HL, two studies in which subjects were exposed to eUVR and two to sUVR. Two randomized controlled trials with a crossover design demonstrated, using a solar simulator, the effectiveness of lip sunscreen in reducing HL after UV exposure. The first study was conducted on 38 patients: it showed that after exposure to artificial ultraviolet, equal to 4 MED, HL developed in 27 patients (71%) treated with placebo. In contrast, when a sun protection factor (SPF) 15 sunscreen was applied during UV exposure, no lesion developed on 35 patients [70]. The second work carried out on 19 individuals, exposed to 4 MED for 10 min of ultraviolet light under artificial conditions, found that sunscreen significantly reduces relapses compared to placebo: one on 19 patients (5%) with sun protection against 11 out of 19 individuals (58%) with placebo [79].

Studies carried out in the natural environment have given different results.

The first work has been carried out in natural conditions in three ski resorts: Park City, Utah (January 21–28) SnowMass, Colorado (February 25 to March 3) and Keystone, Colorado (April 8–15) at a latitude between 40 and 39°. Fifty-one volunteer skiers were analyzed, showing that a SPF 15 sun screen compared to placebo was not effective to prevent reactivation of the virus. HL developed in 3 out of 24 subjects using protection and in 3 out of 27 with placebo [104]. This work was criticized by stating that the UV dose received by volunteer skiers during the trial was 1–3 MED

**21**

**5. Treatment**

tion or minimize its effects?

**5.1 Practical photoprotection strategy**

*Sunlight and Herpes Virus*

*DOI: http://dx.doi.org/10.5772/intechopen.82643*

per day, which is lower than the 4 MED needed to trigger recurrence [70]. Probably due to this limitation, this study is not mentioned in the main guidelines for HL treatment [105]. Furthermore, it is not reported what amount of sunscreen was applied by skiers. However, in the latter two experiments carried out with artificial light the sunscreens were likely applied in a dose sufficient to respect the SPF value [106]. The second randomized, crossover study was carried out in northern Sardinia (Italy) on 20 volunteers who went to beach at a latitude of 40–41° using a sunblock stick with SPF 30. The study was conducted between May and July 2017 around the summer solstice (June 21st) when the sun reaches its highest point in the sky, to make the total amount of solar irradiance equal in the two sequential study periods. For each volunteer the study period lasted 60 days: 30 with protection and 30 without protection. The month with or without product application was randomly assigned to each patient so as 10 subjects started the trial without protection and 10 with protection and the opposite during the following month. During the month when volunteers had to use a protection, they were requested to apply the sunblock stick on the vermilion and lip skin two times consecutively creating a double protective layer before going out or going to the sea. The protection was repeated every 2 h, after eating or drinking, smoking and after a swim. 4 MED were reached and exceeded by volunteers several times during the 2 months of study. In fact, each volunteer remained at the beach at around 12 am with an average of 4.5 ± 0.95 h in the period with stick and 4.3 ± 0.94 h in the period without stick exceeding the aforementioned dose. Results demonstrated that sunscreen is effective in protecting the upper lip from reactivating the HL. In fact, only one volunteer out of 20 had a HL during the period of sunscreen use versus 10 out of 20 without sunscreen during the studied period. One volunteer from the second group reported two sequential HL. The single event during the period with labial photoprotection was unleashed in the last week, the 11 events of the period without photoprotection appeared from the second week of exposure. All lesions were clinically diagnosed with the help of Tzanck's cytodiagnostic examination [107]. In summary, these three studies, even though with a small number of subjects, showed that sunscreens can reduce the relapses caused by HSV

following UVR exposure both in the laboratory and in the open air.

If you suffer from relapsing HSV or you want to reduce the risk of the onset of HZ especially in summer, the most effective way is to avoid sunlight. Obviously, this is not always possible for most people. Even if someone deliberately avoids going to the beach, the face and other exposed parts of the body will still come in contact with direct sunlight throughout the day. What should be done to avoid solar radia-

To minimize the risk of a HS recurrence it is necessary: to perform a gradual and progressive sun exposure; to know what garments to wear; to know the environmental conditions of exposure; to know each skin phototype; to use a protective product against UVB and UVA with SPF suitable for each phototype and environmental conditions. Sun exposure must be gradual and progressive. The ideal would be a tanning obtained with irradiation times that do not induce erythema for long periods, in order to activate mechanisms of natural photoprotection. In fact, it has been shown that sub-erythematous doses of UVB produce a tan. It is advised wearing long trousers and long-sleeved shirts during summer to

#### *Sunlight and Herpes Virus DOI: http://dx.doi.org/10.5772/intechopen.82643*

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

intravenous injection of dexamethasone [98, 101, 103].

To date four studies have been published on sunscreen used by volunteers who suffered from HL, two studies in which subjects were exposed to eUVR and two to sUVR. Two randomized controlled trials with a crossover design demonstrated, using a solar simulator, the effectiveness of lip sunscreen in reducing HL after UV exposure. The first study was conducted on 38 patients: it showed that after exposure to artificial ultraviolet, equal to 4 MED, HL developed in 27 patients (71%) treated with placebo. In contrast, when a sun protection factor (SPF) 15 sunscreen was applied during UV exposure, no lesion developed on 35 patients [70]. The second work carried out on 19 individuals, exposed to 4 MED for 10 min of ultraviolet light under artificial conditions, found that sunscreen significantly reduces relapses compared to placebo: one on 19 patients (5%) with sun protection against 11 out of

Studies carried out in the natural environment have given different results. The first work has been carried out in natural conditions in three ski resorts: Park City, Utah (January 21–28) SnowMass, Colorado (February 25 to March 3) and Keystone, Colorado (April 8–15) at a latitude between 40 and 39°. Fifty-one volunteer skiers were analyzed, showing that a SPF 15 sun screen compared to placebo was not effective to prevent reactivation of the virus. HL developed in 3 out of 24 subjects using protection and in 3 out of 27 with placebo [104]. This work was criticized by stating that the UV dose received by volunteer skiers during the trial was 1–3 MED

**4.5 Do sun-screen reduce HSV recurrence?**

19 individuals (58%) with placebo [79].

manifest. It does not seem that through this mechanism we can identify a "remote" influence that reactivates the virus, but only a local effect of more peripheral virions approaching the skin. In the second pathway, UVR directly determine an imbalance or radiation damage to epidermal and dermal cells, which are stimulated to repair producing transcription factors that in addition to activating cellular gene expression also activate the viral one and also inhibit the stimulus to apoptosis [80]. Especially the cell repair, through the c-Jun and c-Fos transcription factors, activates the HSV transcription promoter (infected cell polypeptide 0), leading to HSV transcription and reactivation [92]. Additionally, these repair pathways circumvent the activity of HSV latency-associated transcript preventing infected neurons from undergoing apoptosis and in turn, reactivating HSV [93]. Despite these models, significant gaps remain in our understanding of how these stimuli correlate with reactivation of the virus resulting in clinical disease. The third pathway is a molecular model that explains how UVR at the body surface results in multiple neuronal effects or hormonal alteration that could be relevant to reactivation. For example, a damage to innervated tissues that results in loss of the neurotrophin-producing cells and changes in the levels of regulatory neuropeptides, neurotrophins, neurotransmitters may occur following UV irradiation [94]. Nerve growth factor (NGF) deprivation was first found to trigger HSV reactivation in primary neuronal models of HSV latency using rat sympathetic neurons [95]. In vivo injection of anti-NGF serum into latently infected rabbits has also been shown to enhance reactivation of HSV [96]. Furthermore, interruption of signals downstream of the NGF receptor triggered reactivation in a variety of in vitro models of HSV latency [97–100], and has been shown to enhance explant mediated reactivation ex vivo [101, 102]. In addition, UV treatment in mice results in increased serum levels of cortisol and may act through a pathway that is similar to psychological stress-induced reactivation. It was also noted that the dexamethasone, a synthetic corticosteroid, stimulates reactivation of HSV-1 both ex vivo and in primary neuronal cultures, and the closely related bovine HSV-1 can also be reactivated in latently infected calves by

**20**

per day, which is lower than the 4 MED needed to trigger recurrence [70]. Probably due to this limitation, this study is not mentioned in the main guidelines for HL treatment [105]. Furthermore, it is not reported what amount of sunscreen was applied by skiers. However, in the latter two experiments carried out with artificial light the sunscreens were likely applied in a dose sufficient to respect the SPF value [106]. The second randomized, crossover study was carried out in northern Sardinia (Italy) on 20 volunteers who went to beach at a latitude of 40–41° using a sunblock stick with SPF 30. The study was conducted between May and July 2017 around the summer solstice (June 21st) when the sun reaches its highest point in the sky, to make the total amount of solar irradiance equal in the two sequential study periods. For each volunteer the study period lasted 60 days: 30 with protection and 30 without protection. The month with or without product application was randomly assigned to each patient so as 10 subjects started the trial without protection and 10 with protection and the opposite during the following month. During the month when volunteers had to use a protection, they were requested to apply the sunblock stick on the vermilion and lip skin two times consecutively creating a double protective layer before going out or going to the sea. The protection was repeated every 2 h, after eating or drinking, smoking and after a swim. 4 MED were reached and exceeded by volunteers several times during the 2 months of study. In fact, each volunteer remained at the beach at around 12 am with an average of 4.5 ± 0.95 h in the period with stick and 4.3 ± 0.94 h in the period without stick exceeding the aforementioned dose. Results demonstrated that sunscreen is effective in protecting the upper lip from reactivating the HL. In fact, only one volunteer out of 20 had a HL during the period of sunscreen use versus 10 out of 20 without sunscreen during the studied period. One volunteer from the second group reported two sequential HL. The single event during the period with labial photoprotection was unleashed in the last week, the 11 events of the period without photoprotection appeared from the second week of exposure. All lesions were clinically diagnosed with the help of Tzanck's cytodiagnostic examination [107]. In summary, these three studies, even though with a small number of subjects, showed that sunscreens can reduce the relapses caused by HSV following UVR exposure both in the laboratory and in the open air.
