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Reactivation of latent virus mals, using primers specific for ICP6. To confirm the presence of the latent wild-type virus in this brain region, PI days Virus shedding RT-PCR PCR was performed on DNA samples extracted from the HSV-1/kos, same tissue using the same primers. A 237-base PCR pro- cornea CdSO 4 Cerebral CdSO 4 Cerebral infection duct corresponding to the wild-type ICP6 gene was infection infection detected without difficulty (Figure 2).
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Herpes simplex virus type-1 (HSV-1) has been used for gene delivery in the nervous system for the treatment of brain tumors and other neurological diseases. In most protocols, recombinant viruses containing the gene of interest are directly injected into the brain. Since many people harbor latent wild-type HSV-1 virus in sensory ganglia and other r...
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Sensory ganglia latently infected with herpes simplex virus (HSV) were transplanted beneath the renal capsule of syngeneic recipients, and the latent infection remaining was investigated. HSV latency-associated transcript (LAT) expression and reactivation of HSV after explant of transplanted dorsal root ganglia were monitored as markers of latency....
Persisting infections are often associated with chronic T cell activation. For certain pathogens, this can lead to T cell exhaustion and survival of what is otherwise a cleared infection. In contrast, for herpesviruses, T cells never eliminate infection once it is established. Instead, effective immunity appears to maintain these pathogens in a sta...
Koi herpesvirus (KHV) has recently been classified as a member of the family of Alloherpesviridae within the order of Herpesvirales. One of the unique features of Herpesviridae is latent infection following a primary infection. However, KHV latency has not been recognized. To determine if latency
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... Antitumor effects of IL-12 and GM-CSF co-expressed in an engineered oncolytic HSV-1 from latency [39][40][41]. In addition, previous studies have shown that rapidly proliferating cancer cells express elevated levels of cellular RNR, which elicits cell cycle alterations and a prolonged S phase in sarcoma, bladder, brain, breast, colorectal, liver, and lung cancers [42][43][44]. ...
Oncolytic viruses selectively replicate and destroy cancer cells while sparing normal cells, prompting their recognition as promising antitumor agents. Herpes simplex virus (HSV) is suitable as an anticancer agent, given its considerable therapeutic gene capacity and excellent safety profile in clinical trials. Interleukin (IL)-12 induces a Th1-type immune response that mediates interferon (IFN)-γ release from natural killer (NK), CD4⁺ and CD8⁺ T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the generation of antigen-presenting cells and promotes dendritic cell differentiation. We established a novel oncolytic HSV-1 (∆6/GM/IL12) co-expressing IL-12 and GM-CSF and tested its effects against a B16-F10 murine melanoma model. ∆6/GM/IL12 administration diminished tumor growth and prolonged survival compared to treatment with ∆6/GM or ∆6/IL12 expressing each individual cytokine. Flow cytometry and histological analysis showed increased activation of CD4⁺ and CD8⁺ T cells in ∆6/GM/IL12-treated mice. Enzyme-linked immunosorbent spot assay showed an increase in the phenotypically characterized IFN-γ-producing cell population in ∆6/GM/IL12-treated mice. Moreover, ∆6/GM/IL12 induced a B16-F10-specific cytotoxic immune response that enhanced IFN-γ production by CD3⁺CD8⁺ T cells. Therefore, IL-12 and GM-CSF from an engineered oncolytic HSV have a synergistic effect, boosting the immune response to increase their antitumor effects.
... 15 Preclinical studies have shown that intracerebral recombinant HSV-1 vectors do not reactivate latent HSV. 16 The HSV therefore seems ideal when it comes to targeting the trigeminal ganglion, in order to induce the production of analgesic polypeptides such as human proenkephalin. ...
According to Centers for Disease Control and Prevention, each year, an estimated 1.7 million Americans sustain a traumatic brain injury (TBI), which frequently leads to chronic craniofacial pain. In this study we examine a gene therapy approach to the treatment of post-TBI craniofacial neuropathic pain using nasal application of a Herpes Simplex Virus-based vector expressing human proenkephalin (SHPE) to target the trigeminal ganglia. Mild TBI was induced in rats by use of a modified Fluid Percussion Model. Two days after mild TBI, following the development of facial mechanical allodynia, animals received either an intranasal application of vehicle or recombinant HSV encoding human preproenkephalin or lacZ reporter gene encoding control vector (SHZ.1). Compared to baseline response thresholds, mild TBI in SHZ.1 or vehicle treated animals induced a robust craniofacial allodynia lasting at least 45 days. On the other hand, nasal SHPE application 2 days post-TBI attenuated facial allodynia, reaching significance by day 4–7 and maintaining this effect throughout the duration of the experiment. Immunohistochemical examination revealed strong expression of human proenkephalin in trigeminal ganglia of SHPE, but not SHZ.1 treated rats. This study demonstrates that intranasal administration of HSV-based gene vectors may be a viable, non-invasive means of treating chronic craniofacial pain, including post-TBI pain.
... In rats infected with wild-type HSV, subsequent intracranial injection of HSV vectors did not lead to viral reactivation of the vector. 54 However, multiple strains of HSV were isolated from the neuronal tissue of a single patient, thus perhaps supporting intratypic recombination rather than successive infection. 33 As an enveloped virus, HSV is inherently unstable in the environment. ...
Viral vector research presents unique occupational health and safety challenges to institutions due to the rapid development of both in vivo and in vitro gene-editing technologies. Risks to human and animal health make it incumbent on institutions to appropriately evaluate viral vector usage in research on the basis of available information and governmental regulations and guidelines. Here we review the factors related to risk assessment regarding viral vector usage in animals and the relevant regulatory documents associated with this research, and we highlight the most commonly used viral vectors in research today. This review is particularly focused on the background, use in research and associated health and environmental risks related to adenoviral, adeno-associated viral, lentiviral, and herpesviral vectors. Copyright 2017 by the American Association for Laboratory Animal Science.
... H erpes simplex virus 1 (HSV-1) is a double-stranded DNA (dsDNA) virus belonging to the Alphaherpesvirus family, which causes oral herpes, encephalitis, keratitis, neonatal herpes, and pneumonia disease, establishing latency in the neurons after acute infection of mucosal tissues (1)(2)(3). Notably, HSV-1 can be isolated from the respiratory tract of immunosuppressed patients and newborn infants, where it induces pneumonitis, resulting in remarkable morbidity and mortality (4). Recent studies have suggested that HSV-1-induced bronchopneumonitis is common in nonimmunocompromised persons who are undergoing continuous mechanical ventilation (5). ...
Caveolin-1 (Cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interaction. Several viruses exploit caveolae to facilitate viral infections. However, the roles of Cav-1 in herpes simplex virus type 1 (HSV-1) infection have not been fully elucidated. Here, we report that Cav-1 down-regulates the expression of inducible nitric oxide (iNOS) and production of nitric oxide (NO) in DCs (Dendritic cells) during HSV-1 infection. As a result, Cav-1 deficiency led to an accelerated elimination of virus and less lung pathological change following HSV-1 infection. This protection was dependent on iNOS and NO production in DCs. Adoptive transfer of DCs with Cav-1 knockdown was sufficient to confer the protection to WT mice. In addition, Cav-1 KO (Cav-1(-/-)) mice treated with an iNOS inhibitor exhibited a significantly reduced survival as compared to the non-treated controls. We found that Cav-1 co-localized with iNOS and HSV-1 in caveolae in HSV-1 infected DCs, suggesting their interaction. Taken together, our results identified Cav-1 as a novel regulator utilized by HSV-1 to evade host antiviral response mediated by NO production. Therefore, Cav-1 could be a valuable target for therapeutic approaches against herpes virus infections.
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... The presence of viral vector can be detected by PCR, allowing also to monitor for mobilization and/or shedding of vector at tissues further from the inoculation site. Recombination of replication-defective vectors with endogenous HSV-1 to produce replication-competent virus has been reported to be undetectable [147] (see section 3.5), but can be monitored by viral culture on epithelial cell lines such as VERO or BHK, or by PCR; definitive molecular verification of recombination would require sequencing of newly formed junctions. Immunostaining for viral antigens after more than four days after inoculation may also reveal any viral gene expression activity such as might occur in the generation of replication-competent virus. ...
... Since the majority of the human population habours HSV-1 in the latent form, the question often arises as to whether HSV-1 vectors can recombine with, and/or reactivate, endogenous wild-type HSV-1 in infected individuals. In two different rat models of latency, intracerebral injection of HSV-1 vectors did not reactivate latent wild-type HSV-1 in either the cerebral or corneal model whereas cadmium sulphate treatment provoked virus mobilization and shedding [147]. Although it should be kept in mind that rats are less susceptible to HSV-1 infection than humans, these results indicate that there is little risk of reactivating latent wild-type HSV-1 by application of replication-defective HSV-1 vectors, at least by intracranial injection. ...
The majority of humans have been infected with Herpes Simplex Virus Type 1 (HSV-1) and harbor its viral DNA in the latent form within neurons for lifetime. This, combined with the absence of serious adverse effects due to HSV-1 derived vectors in clinical trials so far, highlight the potential to use this virus to develop neuronal gene transfer vectors which are transparent to the host, allowing the effects of the transgene to act without interference from the transfer system eg., for functional genomics in basic neuroscience or gene therapy of neurological disorders. On the other hand, other HSV-1 derived vectors which also have a promising perspective in the clinic, are designed to have enhanced cytotoxicity in certain cell types, as in the case of oncolytic vectors. Understanding virus-host interactions is fundamental not only to the success of these gene therapy vectors but also with respect to identifying and minimizing biohazards associated with their use. In this review we discuss characteristics of HSV-1 and gene therapy vectors derived from this virus which are useful to consider in the context of biosafety risk assessment and risk management.
... As already mentioned, HSV spreads along nerves also beyond the first pseudounipolar neuron and may establish latent infection within the brain stem and possibly also in the olfactory brain cortex and related structures of the limbic system (amygdala, hippocampus) as shown in a rabbit model (Kúdelová and Rajčáni 1990) as well as in human CNS samples by in situ hybridization (Rajčáni et al. 1991a). The significance of these preliminary findings was later on widely accepted (Wang et al. 1997) and, therefore, further analyzed. Interestingly, if the specimens from the amygdala removed during stereotactic surgery were cultured, no virus could be rescued as it was the case with the trigeminal ganglion explants. ...
... However, neurons harboring the latent virus and expressing LAT are protected from the superinfecting virus (Mador et al. 2002). Furthermore, superinfection of animals with established latency using another replication-defective (ICP6 minus) HSV-1 mutant did not reactivate the latent virus (Wang et al. 1997). In conclusion, despite extensive experimental research, the main questions-Which routes do the HSV-1 spread into CNS take? ...
... Experiments have been performed to assess this risk in the nervous system. Upon intracerebral administration of replication defective HSV-1 to latently infected rats, reactivation of wildtype HSV-1 from latency has not been observed [96]. ...
Within the Herpesviridae family, Alphaherpesvirinae is an extensive subfamily which contains numerous mammalian and avian viruses. Given the low rate of herpesvirus nucleotide substitution, recombination can be seen as an essential evolutionary driving force although it is likely underestimated. Recombination in alphaherpesviruses is intimately linked to DNA replication. Both viral and cellular proteins participate in this recombination-dependent replication. The presence of inverted repeats in the alphaherpesvirus genomes allows segment inversion as a consequence of specific recombination between repeated sequences during DNA replication. High molecular weight intermediates of replication, called concatemers, are the site of early recombination events. The analysis of concatemers from cells coinfected by two distinguishable alphaherpesviruses provides an efficient tool to study recombination without the bias introduced by invisible or non-viable recombinants, and by dominance of a virus over recombinants.
Intraspecific recombination frequently occurs between strains of the same alphaherpesvirus species. Interspecific recombination depends on enough sequence similarity to enable recombination between distinct alphaherpesvirus species. The most important prerequisite for successful recombination is coinfection of the individual host by different virus strains or species. Consequently the following factors affecting the distribution of different viruses to shared target cells need to be considered: dose of inoculated virus, time interval between inoculation of the first and the second virus, distance between the marker mutations, genetic homology, virulence and latency. Recombination, by exchanging genomic segments, may modify the virulence of alphaherpesviruses. It must be carefully assessed for the biosafety of antiviral therapy, alphaherpesvirus-based vectors and live attenuated vaccines. Copyright
... Moreover, in two different latency models in rats, intracerebral injection of hrR3 did not reactivate latent wt HSV -1 in either the corneal or the cerebral model. This indicates that intracranial injection of partially defective recombinants of HSV -1 may bear little or no risk of reactivating latent wt virus present in sensory ganglia or brain [89], although it must be kept in mind that rats are, in general, less infectable with HSV -1 than humans. ...
Many properties of HSV-1 are especially suitable for using this virus as a vector to treat diseases affecting the central nervous system (CNS), such as Parkinson's disease or malignant gliomas. These advantageous properties include natural neurotropism, high transduction efficiency, large transgene capacity, and the ability of entering a latent state in neurons. Selective oncolysis in combination with modulation of the immune response mediated by replication-conditional HSV-1 vectors appears to be a highly promising approach in the battle against malignant glioma. Helper virus-free HSV/AAV hybrid amplicon vectors have great promise in mediating long-term gene expression in the PNS and CNS for the treatment of various neurodegenerative disorders or chronic pain. Current research focuses on the design of HSV-1-derived vectors which are targeted to certain cell types and support transcriptionally regulatable transgene expression. Here, we review the recent developments on HSV-1-based vector systems and their applications in experimental and clinical gene therapy protocols.
The current state of replication-competent or replication-selective oncolytic viral treatment of malignant astrocytomas is reviewed. This includes studies examining the DNA viruses herpes simplex type I and adenovirus, both of which can be engineered to replicate only in dividing cancer cells, and RNA viruses, including reovirus, measles virus, Newcastle disease virus (NDV), and vesicular stomatitis virus (VSV), some of which replicate selectively in brain tumors because of transformed cellular defects in antiviral immunity and others which require modification to render them nonpathogenic in health brain tissue while destroying resident tumor cells. Also discussed is that local viral expression of cytokines could overcome the immunosuppressive tumor microenvironment and lead to tumor clearance including immune clearance of distant noninfected tumor cells.
