RESUMEN
HSV type 1 (HSV-1) is one of the leading etiologies of sporadic viral encephalitis. Early antiviral intervention is crucial to the survival of herpes simplex encephalitis patients; however, many survivors suffer from long-term neurologic deficits. It is currently understood that HSV-1 establishes a latent infection within sensory peripheral neurons throughout the life of the host. However, the tissue residence of latent virus, other than in sensory neurons, and the potential pathogenic consequences of latency remain enigmatic. In the current study, we characterized the lytic and latent infection of HSV-1 in the CNS in comparison with the peripheral nervous system following ocular infection in mice. We used RT-PCR to detect latency-associated transcripts and HSV-1 lytic cycle genes within the brain stem, the ependyma (EP), containing the limbic and cortical areas, which also harbor neural progenitor cells, in comparison with the trigeminal ganglia. Unexpectedly, HSV-1 lytic genes, usually identified during acute infection, are uniquely expressed in the EP 60 d postinfection when animals are no longer suffering from encephalitis. An inflammatory response was also mounted in the EP by the maintenance of resident memory T cells. However, EP T cells were incapable of controlling HSV-1 infection ex vivo and secreted less IFN-γ, which correlated with expression of a variety of exhaustion-related inhibitory markers. Collectively, our data suggest that the persistent viral lytic gene expression during latency is the cause of the chronic inflammatory response leading to the exhaustion of the resident T cells in the EP.
Asunto(s)
Encefalitis por Herpes Simple/virología , Epéndimo/virología , Herpes Simple/inmunología , Linfocitos T/inmunología , Latencia del Virus/fisiología , Animales , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/inmunología , Epéndimo/inmunología , Citometría de Flujo , Herpesvirus Humano 1/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
UNLABELLED: Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0ΔNLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0ΔNLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality compared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. Moreover, 0ΔNLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechanosensory function. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0ΔNLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency. IMPORTANCE: HSV-1 manifests in a variety of clinical presentations ranging from a rather benign "cold sore" to more severe forms of infection, including necrotizing stromal keratitis and herpes simplex encephalitis. The present study was undertaken to evaluate a novel vaccine to ocular HSV-1 infection not only for resistance to viral replication and spread but also for maintenance of the visual axis. The results underscore the necessity to reconsider strategies that utilize attenuated live virus as opposed to subunit vaccines against ocular HSV-1 infection.
Asunto(s)
Córnea/patología , Vacunas contra el Virus del Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Inmunidad Humoral , Queratitis Herpética/inmunología , Queratitis Herpética/prevención & control , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Córnea/inmunología , Córnea/virología , Femenino , Vacunas contra el Virus del Herpes Simple/administración & dosificación , Herpesvirus Humano 1/patogenicidad , Humanos , Inmunización Pasiva , Queratitis Herpética/virología , Activación de Linfocitos , Ratones , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Proteínas del Envoltorio Viral/administración & dosificación , Proteínas del Envoltorio Viral/inmunología , Esparcimiento de VirusRESUMEN
The subchromosomal region 1q21.1 is one of the hotspots in the human genome for deletions and reciprocal duplications, owing to the existence of hundreds of segmental duplications. Recurrent deletions and duplications in this region are thought to be causative in patients with variable clinical manifestations. Based on the genomic locations, deletions and duplications at the 1q21.1 locus have been associated with distinguishable syndromes: chromosome 1q21.1 deletion syndrome, chromosome 1q21.1 duplication syndrome, and thrombocytopenia-absent radius (TAR) syndrome, which is partially due to deletions at the proximal 1q21.1 region. We report here diverse, recurrent deletions and duplications at the 1q21.1 locus in 36 patients from a cohort of 5,200 individuals. Among the 36 patients, 18 patients carry 1q21.1 deletions, nine individuals have reciprocal duplications at 1q21.1, two patients share an identical short deletion, and the remaining seven possess variable sizes of duplications at the proximal 1q21.1 region. Furthermore, we provide cytogenetic characterization and detailed clinical features for each patient. Notably, duplications at the proximal 1q21.1 region have not been associated with a defined disorder in publications. However, recurrent duplications at the proximal 1q21.1 region among the seven patients strongly suggested that the variants are likely pathogenic. The common phenotypical features of those disorders are also summarized to facilitate clinical diagnoses and genetic counseling.