Prior Corneal Scarification and Injection of Immune Serum are Not Required Before Ocular HSV-1 Infection for UV-B-Induced Virus Reactivation and Recurrent Herpetic Corneal Disease in Latently Infected Mice

Abstract

Purpose Blinding ocular herpetic disease in humans is due to spontaneous reactivation of herpes simplex virus type 1 (HSV-1) from latency, rather than to primary acute infection. Mice latently infected with HSV-1 undergo little or no in vivo spontaneous reactivation with accompanying virus shedding in tears. HSV-1 reactivation can be induced in latently infected mice by several in vivo procedures, with UV-B-induced reactivation being one commonly used method. In the UV-B model, corneas are scarified (lightly scratched) just prior to ocular infection to increase efficiency of the primary infection and immune serum containing HSV-1 neutralizing antibodies is injected intraperitoneally (i.p.) to increase survival and decrease acute corneal damage. Since scarification can significantly alter host gene transcription in the cornea and in the trigeminal ganglia (TG; the site of HSV-1 latency) and since injection of immune serum likely modulates innate and adaptive herpes immunity, we investigated eliminating both treatments. Material and Methods Mice were infected with HSV-1 with or without corneal scarification and immune serum. HSV-1 reactivation and recurrent disease were induced by UV-B irradiation. Results When corneal scarification and immune serum were both eliminated, UV-B irradiation still induced both HSV-1 reactivation, as measured by shedding of reactivated virus in tears and herpetic eye disease, albeit at reduced levels compared to the original procedure. Conclusion Despite the reduced reactivation and disease, avoidance of both corneal scarification and immune serum should improve the clinical relevance of the UV-B mouse model.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…On day 24 (i.e., during the latent phase), the eyes of 15 infected animals that survived acute infection were exposed to UV-B irradiation in order to induce reactivation of HSV-1 from latently infected trigeminal ganglia (TG). UV-B irradiation led to virus shedding in tears and recurrent corneal herpetic disease, as we recently described (5,6). The timeline of HSV-1 infection, UV-B irradiation, and subsequent immunological and virological assays is illustrated in Fig.…”

“…Reactivation of latent HSV-1 was induced in latently infected mice following UV-B irradiation as we recently described (5,6). Briefly, 24 days postinfection, when latency was fully established, anesthetized mice were placed on the transilluminator, and each mouse was positioned on a piece of cardboard containing a hole the same size as the mouse's eye, allowing a single eye to be irradiated by the UV-B source.…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…A formal demonstration that ASYMP CD8 ϩ T EM cells with these functions cause the immunologic control of recurrent herpesvirus infection and disease would require passive transfer studies in HSV-1-infected hosts that develop recurrent disease (14). Such studies are currently ongoing in our laboratory using our mouse model of UV-B-induced recurrent herpetic disease (5,6), and the results will be the subject of future reports.…”

“…After primary (1°) ocular HSV-1 infection, the virus establishes latency in the sensory neurons of human trigeminal ganglia (TG), a state that lasts for the life of the host (1,(4)(5)(6). Sporadic reactivation of the virus from latently infected sensory neurons of TG produces virus shedding in tears, which can lead to either relatively harmless asymptomatic (ASYMP) secondary (2°) reinfection of the cornea (COR) or symptomatic (SYMP) recurrent corneal disease and potentially blinding herpetic stromal keratitis (HSK) (5)(6)(7)(8). The majority of HSVseropositive individuals are ASYMP (9-12).…”

A Tribute to Professor Steven L. Wechsler (1948–2016): The Man and the Scientist

“…They found that microR-H2 acts to help maintain latency and confirmed the hypothesis that at least one of the LAT microRNAs plays a role in HSV-1 latency. Professors Wechsler and BenMohamed also recently developed an improved mouse model of UV-B induced ocular reactivation of HSV-1 (strain Mckrae) [8; 9]. This new UV-B mouse model will allow for detailed investigations of the underlying mechanisms of immune evasion during the latency/reactivation cycle.…”