Decreased reactivation of a herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) mutant using the in vivo mouse UV-B model of induced reactivation

Abstract

Blinding ocular herpetic disease in humans is due to herpes simplex virus type 1 (HSV-1) reactivations from latency, rather than to primary acute infection. The cellular and molecular mechanisms that control the HSV-1 latency-reactivation cycle remain to be fully elucidated. The aim of this study was to determine if reactivation of the HSV-1 latency associated transcript (LAT) deletion mutant (dLAT2903) was impaired in this model, as it is in the rabbit model of induced and spontaneous reactivation and in the explant TG induced reactivation model in mice. The eyes of mice latently infected with wild type HSV-1 strain McKrae (LAT(+) virus) or dLAT2903 (LAT(−) virus) were irradiated with UV-B and reactivation was determined. We found that compared to LAT(−) virus, LAT(+) virus reactivated at a higher rate as determined by shedding of virus in tears on days 3 to 7 after UV-B treatment. Thus, the UV-B induced reactivation model of HSV-1 appears to be a useful small animal model for studying the mechanisms involved in how LAT enhances the HSV-1 reactivation phenotype. The utility of the model for investigating the immune evasion mechanisms regulating the HSV-1 latency/reactivation cycle and for testing the protective efficacy of candidate therapeutic vaccines and drugs are discussed.

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.…”

“…6B and C) FIG 5 Coexpression of a neurotropic recombinant adeno-associated virus type 8 (fAAV8) bearing GFP and CXCL10 chemokine in latently infected trigeminal ganglia of CXCL10 Ϫ/Ϫ mice following topical ocular application. CXCL10 Ϫ/Ϫ mice (n ϭ 20) were ocularly infected using 2 ϫ 10 5 wild-type McKrae (HSV-1) strain.…”

“…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.…”

Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia

“…Moreover, in natural infection, HSV-1 reactivates as a consequence of stress induced by physical injury to neurons [e.g., UV light exposure (30,31)] or cytokines [e.g., IL6 (32,33)] induced by hormonal or emotional stress (34,35). In the model system used in these studies, the primary stress is excision of ganglia, and the induction of ATF3 appears to be at least one of the induced responses to stress.…”

“…Current consensus holds that the function of LAT and, most likely, of the miRNAs is to maintain the integrity of the neuron to maintain the virus in a silent state (38,39). In the absence of LAT, neurons harboring latent virus succumb to apoptosis (31). NGF is similarly required for the maintenance of neurons; withdrawal of NGF results in apoptosis (40,41).…”