Ultraviolet Light Induces Reactivation in a Murine Model of Cutaneous Herpes Simplex Virus-1 Infection¶

Abstract

We have developed a model of cutaneous herpes simplex virus-1 (HSV-1) reactivation in SKH-1 hairless mice which closely mimics the condition in humans. Sixty plaque-forming units of HSV-1 strain 17 syn+ were applied to a superficially abraded area on the lateral body wall. More than 85% of mice developed primary HSV-1 infection characterized by a zosteriform pattern of cutaneous vesiculation and ulceration. Approximately one-third of mice with primary skin lesions succumbed to neurologic disease and in the remaining mice cutaneous lesions healed completely. Subsequent exposure of healed areas to two minimal inflammatory doses of UV resulted in recrudescence of skin lesions in the irradiated areas in almost 60% of mice. Lesions appeared approximately 4 days after irradiation, persisted for 3-5 days and then resolved completely. Reactivation rarely resulted in death due to neurologic disease. Primary lesions had a histologic appearance typical of cutaneous HSV-1 infection with vesicles and focal epithelial necrosis accompanied by the formation of epithelial syncytial cells and the presence of herpetic intranuclear inclusion bodies. In primary lesions HSV-1 was demonstrated by immunohistochemistry, polymerase chain reaction and culture. In reactivated lesions epithelial syncytia and inclusion bodies were not seen; however, virus was demonstrable by polymerase chain reaction and culture. Exposure of the uninfected side to UV did not stimulate disease recurrence suggesting that local effects of UV rather than systemic immunosuppression were responsible for reactivation. Reactivation could also be obtained with two minimal inflammatory doses of UV from a UV-340 light source which emits light approximating the solar spectrum.

DNA damage promotes herpes simplex virus-1 protein expression in a neuroblastoma cell line

“…It has been shown that UV can induce reactivation of HSV-1 virus from a mouse model (Goade et al , 2001) and this is supported by the finding of Ramos-Espinosa et al showing the high susceptibility of neurons to ultraviolet mediated DNA damage compared to reactive oxygen species mediated damage (Ramos-Espinosa et al , 2012). Neurons are highly metabolic and produce high levels of ROS which can damage DNA and deficiency in DNA damage repair pathways in neurons is associated with many neurological diseases (Fishel et al , 2007).…”

“…In contrast, HSV-1 infection of differentiated neurons does not trigger the cell DDR (Lilley et al , 2005) and Fig 3. However, it has been shown that the HSV-1 genome can become reactivated by ultraviolet light (UV)-induced DNA damage in vivo (Goade et al , 2001; Ichihashi et al , 2004; Laycock et al , 1991; Loiacono et al , 2003; Shimeld et al , 1990), and in vitro (Zurlo and Yager, 1984) systems. Our results show that cellular DNA damage induced by a topoisomerase II enzyme inhibitor can enhance viral protein expression in a neuroblastoma cell line in which HSV-1 infection did not trigger the DNA damage response pathway, as measured by γ-H2Ax induction (Fig 3).…”

“…For such a system, ultraviolet light or irradiation or a non-cell-cycling-dependent drug may be used to induce DNA damage. It is well established that ultraviolet light can induce HSV-1 reactivation (Goade et al , 2001). UV causes DNA damage through production of cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4 PP), which can lead to the induction of the ATM/ATR pathways through DNA breaks (Rastogi et al , 2010; Sinha and Hader, 2002).…”

“…It is known that DNA damage caused by irradiation can induce HSV-1 reactivation in animal (Goade et al , 2001; Laycock et al , 1991; Shimeld et al , 1990; Suzuki et al , 1994) and cellular models (Colgin et al , 2001; Zurlo and Yager, 1984). Interestingly, HSV-1 infection of non-neuronal cells induces the ATM (ataxia telangiectasia mutated) branch of the DNA damage pathway and abrogation of components of this pathway leads to a decrease in HSV-1 infection (Lilley et al , 2005).…”

Influence of Galectin-9/Tim-3 Interaction on Herpes Simplex Virus-1 Latency

“…Raised levels of galectins that include Gal-9 have been reported in some stress situations (36–39), conditions where some heat shock proteins are elevated as well in some acute infections (40) that include HSV (41, 42). So called stress situations are a well recognized prequel to HSV reactivation, which can result in disease, or be without lesions (43, 44). Whether or not the human stress scenarios include changes in levels of Gal-9 prior to HSV reactivation merits investigation.…”