Immune control of herpes simplex virus during latency

Khanna, Kamal M.; Lepisto, Andrew J.; Decman, Vilma; Hendricks, Robert L.

doi:10.1016/j.coi.2004.05.003

Cited by 125 publications

(120 citation statements)

References 56 publications

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“…In skin the immunoreactive cells responsible for controlling the transmitted HSV include the normal constituents of the squamous epidermis, keratinocytes and LC, and infiltrating cells. In particular HSV-specific CD4 and CD8 T lymphocytes play a central role in controlling primary and recurrent HSV infections in humans and in primary disease in murine models (where human specimens are difficult to obtain); in recovery from infection as well as in restricting HSV reactivation and spread in the nervous system [45][46][47][48]. In human recurrent disease, there is a temporal sequence of cellular infiltration, first predominantly monocyte/macrophages and CD4 lymphocytes and later predominantly CD8 lymphocytes, as shown by immunohistochemistry and direct T-cell cloning from lesions biopsied serially [43].…”

Section: Subsets In Innate and Adaptive Immunity To Hsvmentioning

confidence: 99%

Langerhans cells and viral immunity

2008

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Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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Section: Subsets In Innate and Adaptive Immunity To Hsvmentioning

confidence: 99%

Langerhans cells and viral immunity

2008

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“…These might, for example, involve reorganization of ND-10 domains (viral DNA docking sites) and sequestration of transcription factors in response to IFNγ (Griffin, 2003;Khanna et al, 2004), phosphorylation of the translation regulator ieFα, and activation of PKR-related multi-viral mechanisms (Scheuner et al, 2003;Baltzis et al, 2004;Bonizzi et al, 2004;Hsu et al, 2004;Isler et al, 2005). However, it remains to be seen whether more specifically gene expression is affected in transduced cells.…”

Section: Discussionmentioning

confidence: 99%

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

et al. 2006

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First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of antiadenovirus immune responses expression in the brain lasts 6-18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1 × 10 7 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1 × 10 7 -1 × 10³ iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8 + T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 × 10 7 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.

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“…The molecular mechanisms underlying HSV latency and reactivation in the CNS are poorly understood but are believed to be controlled by the immune system. 41,42 Interestingly, the presence of actively replicating HSV-1 mRNA has been associated with acute clinical attacks in patients with relapsingremitting MS. 43 This suggests that HSV-1 reactivation may exacerbate the clinical presentation of MS, possibly by virus-induced demyelination. 44 Consistent with this observation and the results reported here, recent experimental studies have shown that human oligodendrocytelike cells are highly susceptible to HSV-1 infection, 45 and that differences in virus-host cell interactions, and hence HSV-1 susceptibility, are probably genetically determined.…”

Section: Discussionmentioning

confidence: 99%

Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis

et al. 2006

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Discrepant findings have been reported regarding an association of the apolipoprotein E (APOE) gene with the clinical course of multiple sclerosis (MS). To resolve these discrepancies, we examined common sequence variation in six candidate genes residing in a 380-kb genomic region surrounding and including the APOE locus for an association with MS severity. We genotyped at least three polymorphisms in each of six candidate genes in 1540 Caucasian MS families (729 single-case and multiple-case families from the United States, 811 single-case families from the UK). By applying the quantitative transmission/ disequilibrium test to a recently proposed MS severity score, the only statistically significant (P ¼ 0.003) association with MS severity was found for an intronic variant in the Herpes Virus Entry Mediator-B Gene (PVRL2). Additional genotyping extended the association to a 16.6 kb block spanning intron 1 to intron 2 of the gene. Sequencing of PVRL2 failed to identify variants with an obvious functional role. In conclusion, the analysis of a very large data set suggests that genetic polymorphisms in PVRL2 may influence MS severity and supports the possibility that viral factors may contribute to the clinical course of MS, consistent with previous reports.

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Immune control of herpes simplex virus during latency

Cited by 125 publications

References 56 publications

Langerhans cells and viral immunity

Langerhans cells and viral immunity

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis

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