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Background After kidney transplantation, immunosuppressive therapy causes impaired cellular immune defense leading to an increased risk of viral complications. Trough level monitoring of immunosuppressants is insufficient to estimate the individual intensity of immunosuppression. We have already shown that virus-specific T cells (Tvis) correlate with control of virus replication as well as with the intensity of immunosuppression. The multicentre IVIST01-trial should prove that additional steering of immunosuppressive and antiviral therapy by Tvis levels leads to better graft function by avoidance of over-immunosuppression (for example, viral infections) and drug toxicity (for example, nephrotoxicity). Methods/design The IVIST-trial starts 4 weeks after transplantation. Sixty-four pediatric kidney recipients are randomized either to a non-intervention group that is only treated conservatively or to an intervention group with additional monitoring by Tvis. The randomization is stratified by centre and cytomegalovirus (CMV) prophylaxis. In both groups the immunosuppressive medication (cyclosporine A and everolimus) is adopted in the same target range of trough levels. In the non-intervention group the immunosuppressive therapy (cyclosporine A and everolimus) is only steered by classical trough level monitoring and the antiviral therapy of a CMV infection is performed according to a standard protocol. In contrast, in the intervention group the dose of immunosuppressants is individually adopted according to Tvis levels as a direct measure of the intensity of immunosuppression in addition to classical trough level monitoring. In case of CMV infection or reactivation the antiviral management is based on the individual CMV-specific immune defense assessed by the CMV-Tvis level. Primary endpoint of the study is the glomerular filtration rate 2 years after transplantation; secondary endpoints are the number and severity of viral infections and the incidence of side effects of immunosuppressive and antiviral drugs. Discussion This IVIST01-trial will answer the question whether the new concept of steering immunosuppressive and antiviral therapy by Tvis levels leads to better future graft function. In terms of an effect-related drug monitoring, the study design aims to realize a personalization of immunosuppressive and antiviral management after transplantation. Based on the IVIST01-trial, immunomonitoring by Tvis might be incorporated into routine care after kidney transplantation. Trial Registration EudraCT No: 2009-012436-32, ISRCTN89806912 (17 June 2009).

The relationship between peripheral and recirculating memory cells remains mostly undefined. Carbone and colleagues present evidence of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry. Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry.

T-cell migration is subset-specific T cells are crucial to immunity at surface tissues such as skin, which represent entry points for many infectious agents. Migration and targeting to these specific regions is thought to be a key to efficient immune protection. Gebhardt et al . provide evidence for differential migration of helper and killer T-cell subsets after local skin infection with herpes simplex virus, with helper and killer memory T cells segregating to dermis and epidermis respectively. CD4 + T cells, through their ability to access the circulation, are thought to be responsible for providing protection distal to the primary site of infection. Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes 1 , resulting in memory T cells that provide local and systemic protection 2 . Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body 3 . However, T-cell immunity consists of separate CD4 + helper T cells and CD8 + killer T cells, with distinct effector and memory programming requirements 4 . Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4 + and CD8 + T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets; a slow-moving population of sequestered CD8 + T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4 + T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4 + T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4 + and CD8 + subsets.

Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons.

Within the oncolytic virus field, the extent of virus replication that is essential for immune stimulation to control tumor growth remains unresolved. Using infected cell protein 0 (ICP0)-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 viruses (dICP0 and dNLS) that show differences in their in vitro replication and cytotoxicity, we investigated the inherent features of oncolytic HSV viruses that are required for potent antitumor activity. In vitro, the HSV-2 vectors showed rapid cytotoxicity despite lower viral burst sizes compared to HSV-1 vectors. In vivo, although both of the dICP0 vectors initially replicated to a similar level, HSV-1 dICP0 was rapidly cleared from the tumors. In spite of this rapid clearance, HSV-1 dICP0 treatment conferred significant survival benefit. HSV-1 dICP0–treated tumors showed significantly higher levels of danger-associated molecular patterns that correlated with higher numbers of antigen-presenting cells within the tumor and increased antigen-specific CD8+ T-cell levels in the peripheral blood. This study suggests that, at least in the context of oncolytic HSV, the initial stages of immunogenic virus replication leading to activation of antitumor immunity are more important than persistence of a replicating virus within the tumor. This knowledge provides important insight for the design of therapeutically successful oncolytic viruses.

We have previously demonstrated safety of G207, a doubly mutated (deletion of both γ134.5 loci, insertional inactivation of UL39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score ≥70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 × 109 plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

Dendritic cells (DCs) express multiple Toll-like receptors (TLR) in distinct cellular locations. Herpes simplex viruses (HSV) have been reported to engage both the surface TLR2 and intracellular TLR9 in conventional DCs. However, the contributions of these TLRs in recognition of HSV and the induction of proinflammatory cytokines in DCs remain unclear. Here, we demonstrate that a rare population of HSV, both in laboratory strains and in primary clinical isolates from humans, has the capacity to activate TLR2. This virus population is recognized through both TLR2 and TLR9 for the induction of IL-6 and IL-12 secretion from bone marrow-derived DCs. Further, we describe a previously uncharacterized pathway of viral recognition in which TLR2 and TLR9 are engaged in sequence within the same DC. Live viral infection results in two additional agonists of TLR2 and TLR9. These results indicate that in cells that express multiple TLRs, pathogens that contain multiple pathogenassociated molecular patterns can be detected in an orchestrated sequence and suggest that the innate immune system in DCs is optimized to linking uptake and degradation of pathogens to microbial recognition.

Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are agents that mediate antitumor activity by directly killing tumor cells and inducing immune responses. Talimogene laherparepvec is an oncolytic herpes simplex virus type 1 (oHSV), approved for the treatment of recurrent melanoma, and the virus encodes the human cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). A significant advantage of oncolytic viruses is the ability to deliver therapeutic payloads to the tumor site that can help drive antitumor immunity. While cytokines are especially interesting as payloads, the optimal cytokine(s) used in oncolytic viruses remains controversial. In this review, we highlight preliminary data with several cytokines and chemokines, including GM-CSF, interleukin 12, FMS-like tyrosine kinase 3 ligand, tumor necrosis factor α, interleukin 2, interleukin 15, interleukin 18, chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 4, or their combinations, and show how these payloads can further enhance the antitumor immunity of oHSV. A better understanding of cytokine delivery by oHSV can help improve clinical benefit from oncolytic virus immunotherapy in patients with cancer.

Herpes simplex virus (HSV) has coevolved with Homo sapiens for over 100,000 years, maintaining a tenacious presence by establishing lifelong, incurable infections in over half the human population. As of 2024, an effective prophylactic or therapeutic vaccine for HSV remains elusive. In this review, we independently screened PubMed, EMBASE, Medline, and Google Scholar for clinically relevant articles on HSV vaccines. We identified 12 vaccines from our literature review and found promising candidates across various classes, including subunit vaccines, live vaccines, DNA vaccines, and mRNA vaccines. Notably, several vaccines—SL-V20, HF10, VC2, and mRNA-1608—have shown promising preclinical results, suggesting that an effective HSV vaccine may be within reach. Additionally, several other vaccines such as GEN-003 (a subunit vaccine from Genocea), HerpV (a subunit vaccine from Agenus), 0ΔNLS/RVx201 (a live-attenuated replication-competent vaccine from Rational Vaccines), HSV 529 (a replication-defective vaccine from Sanofi Pasteur), and COR-1 (a DNA-based vaccine from Anteris Technologies) have demonstrated potential in clinical trials. However, GEN-003 and HerpV have not advanced further despite promising results. Continued progress with these candidates brings us closer to a significant breakthrough in preventing and treating HSV infections.

Background Oncolytic viruses have been proposed to be employed as a potential treatment of cancer. Well targeted, they will serve the purpose of cracking tumor cells without causing damage to normal cells. In this category of oncolytic viral drugs human pathogens herpes simplex virus (HSV) is especially suitable for the cause. Although most viral infection causes antiviral reaction in the host, HSV has multiple mechanisms to evade those responses. Powerful anti-tumor effect can thus be achieved via genetic manipulation of the HSV genes involved in this evading mechanism, namely deletions or mutations that adapt its function towards a tumor microenvironment. Currently, oncolytic HSV (oHSV) is widely use in clinical; moreover, there’s hope that its curative effect will be further enhanced through the combination of oHSV with both traditional and emerging therapeutics. Results In this review, we provide a summary of the HSV host antiviral response evasion mechanism, HSV expresses immune evasion genes such as ICP34.5, ICP0, Us3, which are involved in inducing and activating host responses, so that the virus can evade the immune system and establish effective long-term latent infection; we outlined details of the oHSV strains generated by removing genes critical to viral replication such as ICP34.5, ICP0, and inserting therapeutic genes such as LacZ , granulocyte macrophage colony-stimulating factor (GM-CSF); security and limitation of some oHSV such G207, 1716, OncoVEX, NV1020, HF10, G47 in clinical application; and the achievements of oHSV combined with immunotherapy and chemotherapy. Conclusion We reviewed the immunotherapy mechanism of the oHSV and provided a series of cases. We also pointed out that an in-depth study of the application of oHSV in cancer treatment will potentially benefits cancer patients more.