SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus.

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.

Herpesvirus Infections Potentiated by Biologics.

Herpesviruses such as herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), and cytomegalovirus (CMV) maintain lifelong latency in the host after primary infection and can reactivate periodically either as asymptomatic viral shedding or as clinical disease. Immunosuppression, including biologic therapy, may increase frequency and severity of herpesvirus reactivation and infection. Licensed biologics are reviewed regarding their risks of potentiating HSV, VZV, and CMV reactivation and infection. Approaches to prophylaxis against HSV, VZV, and CMV infection or reactivation are discussed.

Human herpesvirus 8-unrelated primary effusion lymphoma-like lymphoma following tyrosine kinase inhibitor treatment for chronic myelogenous leukemia.

A 69-year-old man was diagnosed with chronic myelogenous leukemia (CML) and treated with dasatinib. After two years on dasatinib, the patient achieved complete molecular response, but dasatinib treatment was discontinued due to exacerbation of pleural effusion. Nilotinib and imatinib were started but stopped due to an increase in pleural effusion. Thoracentesis was performed and he was diagnosed with human herpesvirus 8-unrelated primary effusion lymphoma (PEL)-like lymphoma. Complex chromosomal abnormality, including BCL6 rearrangement, was found on chromosome analysis. To the best of our knowledge, this is the first report of PEL-like lymphoma following tyrosine kinase inhibitor treatment for CML.

Recent advances in the understanding of severe cutaneous adverse reactions.

Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the last decade. This review explores evolving knowledge of the immunopathogenic mechanisms, pharmacogenomic associations, in vivo and ex vivo diagnostics for causality assessment, and medication cross-reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematized framework for translating epidemiological, clinical and immunopathogenetic advances into preventive efforts and improved outcomes for patients.

Effects of the synthetic corticosteroid dexamethasone on bovine herpesvirus 1 productive infection.

Sensory neurons are a primary site for life-long latency of bovine herpesvirus 1 (BoHV-1). The synthetic corticosteroid dexamethasone induces reactivation from latency and productive infection, in part because the BoHV-1 genome contains more than 100 glucocorticoid receptor (GR) responsive elements (GREs). Two GREs in the immediate early transcription unit 1 promoter are required for dexamethasone induction. Recent studies also demonstrated that the serum and glucocorticoid receptor protein kinase (SGK) family stimulated BoHV-1 replication. Consequently, we hypothesized that dexamethasone influences several aspects of productive infection. In this study, we demonstrated that dexamethasone increased expression of the immediate early protein bICP4, certain late transcripts, and UL23 (thymidine kinase) by four hours after infection. SGK1 expression and Akt phosphorylation were also stimulated during early stages of infection and dexamethasone treatment further increased this effect. These studies suggest that stress, as mimicked by dexamethasone treatment, has the potential to stimulate productive infection by multiple pathways.

2,3,7,8-tetrachlorodibenzo-p-dioxin and the viral infection.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread highly toxic environmental contaminant, suppresses immune response and leads to an increased susceptibility to infectious agents. In particular, several studies have provided evidence that TCDD decreases resistance to numerous viruses. Indeed, in vivo and in vitro investigations showed that the presence of TCDD is able to interfere with the replication of both human and animal viruses, such as influenza A viruses, coxsackie virus B3, immunodeficiency virus type-1 (HIV-1), cytomegalovirus (CMV), herpes simplex II, and bovine herpesvirus 1. Moreover, TCDD could induce an exacerbation of latent infection produced by HIV-1, CMV or Epstein-Barr virus. In this review, we first describe the general effects of TCDD exposure on mammalian cells, then we focus on its influence on the viral infections. Overall, the available data support the concept that TCDD exposure may act as an additional risk factor in promoting of viral diseases.

Oncogenic γ Herpesviruses EBV and HHV8 in Kidney Transplantation.

Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) are γ herpesviruses associated with post-transplant malignancies in kidney transplant recipients. EBV is associated with post-transplantation lymphoproliferative disorder (PTLD), with increased risk in EBV-seronegative patients on intensified immunosuppression. Human herpesvirus-8 is associated with Kaposi's sarcoma (KS), with an increased risk in certain patient populations. Diagnosis of PTLD and KS relies on tissue biopsy. The mainstay of therapy for both PTLD and Kaposi's sarcoma is a reduction of immunosuppression, and in the case of PTLD, consideration of rituximab. Chemotherapy, radiation therapy, or surgery is provided for disseminated or recalcitrant disease. The prognoses vary depending on the type of malignancy identified and stage of disease.

Infectious Complications With the Use of Biologic Response Modifiers in Infants and Children.

Biologic response modifiers (BRMs) are substances that interact with and modify the host immune system. BRMs that dampen the immune system are used to treat conditions such as juvenile idiopathic arthritis, psoriatic arthritis, or inflammatory bowel disease and often in combination with other immunosuppressive agents, such as methotrexate and corticosteroids. Cytokines that are targeted include tumor necrosis factor α; interleukins (ILs) 6, 12, and 23; and the receptors for IL-1α (IL-1A) and IL-1ß (IL-1B) as well as other molecules. Although the risk varies with the class of BRM, patients receiving immune-dampening BRMs generally are at increased risk of infection or reactivation with mycobacterial infections (Mycobacterium tuberculosis and nontuberculous mycobacteria), some viral (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, hepatitis B) and fungal (histoplasmosis, coccidioidomycosis) infections, as well as other opportunistic infections. The use of BRMs warrants careful determination of infectious risk on the basis of history (including exposure, residence, and travel and immunization history) and selected baseline screening test results. Routine immunizations should be given at least 2 weeks (inactivated or subunit vaccines) or 4 weeks (live vaccines) before initiation of BRMs whenever feasible, and inactivated influenza vaccine should be given annually. Inactivated and subunit vaccines should be given when needed while taking BRMs, but live vaccines should be avoided unless under special circumstances in consultation with an infectious diseases specialist. If the patient develops a febrile or serious respiratory illness during BRM therapy, consideration should be given to stopping the BRM while actively searching for and treating possible infectious causes.

Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the risks of herpes zoster (HZ) and herpes simplex virus (HSV) infection associated with tofacitinib compared with biologic agents among patients with rheumatoid arthritis (RA). METHODS: Using health plan data from 2010 to 2014, patients with RA initiating tofacitinib or biologics with no history of HZ or HSV were identified, as were incident cases of HZ or HSV. Crude incidence rates were calculated by drug exposure. Cox proportional hazards models evaluated the adjusted association between tofacitinib and HZ, and a composite outcome of HZ or HSV. RESULTS: A total of 2526 patients initiating tofacitinib were compared with initiations of other biologics: anti-tumour necrosis factor (TNF) (n=42 850), abatacept (n=12 305), rituximab (n=5078) and tocilizumab (n=6967). Patients receiving tofacitinib were somewhat younger (mean age 55 years) versus those on other biologics, and somewhat less likely to use concomitant methotrexate (MTX) (39% vs 43%-56%, depending on drug). Crude incidence of HZ associated with tofacitinib was 3.87/100 patient-years (py). After multivariable adjustment, HZ risk was significantly elevated, HR 2.01 (95% CI 1.40 to 2.88) compared with abatacept. Rates and adjusted HRs for all other RA biologics were comparable with each other and abatacept. Older age, female sex, prednisone >7.5 mg/day, prior outpatient infection and greater number of hospitalisations were also associated with increased HZ risk. Incidence rates for the combined outcome were greatest for tofacitinib (7.61/100 py) and also significantly elevated after adjustment (HR=1.40, 95% CI 1.09 to 1.81). CONCLUSIONS: The rate of zoster associated with tofacitinib was approximately double that observed in patients using biologics.

Effects of cyclophosphamide myelosuppression in adult dogs with latent canine herpesvirus-1 infection.

Latent canine herpesvirus-1 (CHV-1) infection is common in domestic dogs, but triggers for viral reactivation and recrudescent CHV-1 disease are poorly understood. Cyclophosphamide is a potent immunosuppressive and myelosuppressive agent used for the therapy of a variety of neoplastic and immune-mediated canine disorders. Cyclophosphamide (200mg/m(2)) was administered to mature dogs latently infected with CHV-1 to determine its potential to induce recurrent CHV-1 disease and viral shedding. Non-infected dogs and dogs recovered from experimental primary ocular CHV-1 infection with experimentally confirmed latent CHV-1 infection were divided into groups and administered cyclophosphamide or placebo. Dogs were monitored for myelosuppression and viral reactivation for 28days using clinical and virological outcome measures. Clinical ophthalmic and in vivo ocular confocal microscopic examinations were performed at intervals. Samples were collected for CHV-1 polymerase chain reaction (PCR), CHV-1 virus neutralizing (VN) antibody, and hemogram assays. Myelosuppression (i.e., decreased total leukocyte, segmented neutrophil, and erythrocyte counts) was detected on study day 7 in dogs administered cyclophosphamide, but not dogs administered placebo. There were no abnormalities suggestive of recurrent CHV-1 ocular disease during clinical ophthalmic or in vivo confocal microscopic examination in any dogs during the study. Ocular CHV-1 shedding was not detected by PCR and CHV-1 VN titers remained stable in all dogs. Following study conclusion, the presence of reactivatable latency was reconfirmed in the infected dogs by administering systemic prednisolone. Myelosuppression elicited by a single dose of cyclophosphamide does not result in detectable recurrent ocular CHV-1 infection in adult dogs with experimentally induced latent CHV-1 infection.

Fingolimod: an oral disease-modifying therapy for relapsing multiple sclerosis.

This paper presents a summary of the current knowledge of the mechanism of action of fingolimod (FTY720; Gilenya®; Novartis Pharma Stein AG, Stein, Switzerland) and the phase 2 and 3 studies that have been performed on the drug. This study will discuss specific safety issues that should be considered when initiating this therapy. Multiple sclerosis (MS), an inflammatory disease of the central nervous system, is considered to be a leading cause of neurologic disability in young adults, and predominantly affects young women. The past two decades have seen significant growth in therapeutic options for relapsing forms of MS, including FTY720. Fingolimod (FTY720) is a sphingosine-1-phosphate receptor modulator, and currently the approved dosage is 0.5 mg daily. Notable side effects include bradycardia in the first hours after administration and macular edema. There may be an increased risk of herpetic infections (varicella zoster virus and herpes simplex virus) associated with this medication. This oral therapy has been shown to be effective in double-blind, placebo-controlled studies, and in trials comparing it to weekly interferon beta-1a therapy. However, the long-term efficacy and safety of this oral medication in relapsing MS, including the effect on reduction of disability progression and cognitive decline, remains to be established.

An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpesviridae.

Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3ß (GSK-3ß), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.

Visceral involvements and long-term sequelae in drug-induced hypersensitivity syndrome.

Drug-induced hypersensitivity syndrome (DIHS) is a severe systemic reaction with several herpesvirus reactivations. Multiple organ failures appear during the course of the disease. The severity of DIHS is determined by the degree of visceral involvement. Autoimmune diseases also develop several months to years after the apparent clinical resolution of DIHS.

Neuropatogênese experimental da infecção pelo herpesvírus bovino tipo 5 em coelhos: [revisão] / Experimental neuropathogenesis of bovine herpesvirus 5 infection in rabbits: [revision]

Vários aspectos da biologia do herpesvírus bovino tipo 5 (BoHV-5) têm sido estudados em coelhos, que desenvolvem infecção aguda e doença neurológica após inoculação experimental. A infecção aguda é seguida pelo estabelecimento de infecção latente, que pode ser reativada natural ou artificialmente. Os primeiros experimentos nesta espécie estabeleceram um protocolo de inoculação e monitoramento da infecção, e caracterizaram os principais aspectos virológicos, clínicos e patológicos da infecção aguda. A patogenia da infecção aguda, desde a replicação viral nos sítios de inoculação, vias e cinética de transporte viral até o encéfalo, distribuição e replicação viral no sistema nervoso central (SNC), tropismo celular e tecidual, manifestações clínicas e patologia no SNC foram detalhadamente estudados nestes animais. Posteriormente, vários aspectos biológicos e moleculares da infecção latente também foram elucidados a partir de inoculações de coelhos. Os coelhos também têm sido utilizados para estudar o fenótipo (neuroinvasividade, neurovirulência) de isolados de campo e de cepas vacinais recombinantes, proteção por imunidade passiva, proteção vacinal, eficácia de drogas anti-virais e terapêuticas de suporte da infecção neurológica. Este modelo experimental também foi utilizado para o estudo da origem e distribuição dos estímulos elétricos produzidos durante as convulsões - uma característica da infecção neurológica pelo BoHV-5 -, e para testes de medicamentos anti-convulsivantes. Ressalvadas as diferenças que certamente existem entre bovinos - os hospedeiros naturais - e coelhos, as observações oriundas deste modelo experimental tem contribuído sobremaneira para o conhecimento da biologia do BoHV-5. O presente trabalho apresenta uma coletânea de resultados e observações, publicadas ou não pelo grupo, ao longo de mais de uma década, envolvendo inoculações de coelhos para estudar diversos aspectos da infecção pelo BoHV-5.

Several aspects of the biology of bovine herpesvirus 5 (BoHV-5) have been studied in rabbits, which develop acute infection and neurological disease upon experimental inoculation. The acute infection is followed by the establishment of latent infection, which can be naturally or artificially reactivated. The first experiments in rabbits established a protocol for virus inoculation and monitoring the infection, and characterized the main virological, clinical and pathological aspects of the acute infection. The pathogenesis of acute infection, from the initial viral replication at site of inoculation, pathways and kinetics of viral transport to the brain, distribution and virus replication in the central nervous system (CNS), cellular and tissue tropism, clinical signs and CNS pathology have been extensively studied using this animal model. Subsequently, several biological and molecular aspects of latent BoHV-5 infection have also been elucidated upon inoculation of rabbits. Rabbits have also been used to investigate the phenotype (neuroinvasiveness, neurogrowth) of field isolates and recombinant vaccine candidates, protection by passive immunity, vaccine protection, the efficacy of anti-viral drugs and support therapies for neurological disease. This animal model was also used to investigate the origin and distribution of electric impulses involved in seizures - a hallmark of BoHV-5 induced neurological infection - and also to test the efficacy of anti-convulsivants. In spite of the possible differences between rabbits and cattle - the natural host of the virus - the observations taken from this experimental model have greatly contributed to the knowledge of the biology of BoHV-5 infection. The present article presents a review of the main published and unpublished results and observations by our group, comprising more than a decade of studies on the pathogenesis of BoHV-5 infection in the rabbit model.

Treatment of gammaherpesvirus-related neoplastic disorders in the immunosuppressed host.

Neoplastic disease is a frequent complication in patients with acquired immunodeficiency disease (AIDS) and other immunodeficiencies. Many such neoplasms are caused by either Epstein-Barr virus (EBV) or Kaposi's sarcoma-associated herpes virus (KSHV). The treatment of such patients can be challenging. At the same time, the viral origin of these tumors offers targets to develop pathogenesis-based therapies. Standard therapies for these diseases involve such approaches as treating the underlying immunodeficiency, cytotoxic chemotherapy, and immunologic antitumor therapy. Novel therapy approaches include specific immune therapy and anti-angiogenesis approaches, now under development.

Herpes virus infections occur frequently following treatment with fludarabine: results of a prospective natural history study.

We performed a prospective infectious natural history study of 21 patients with low-grade lymphoproliferative disorders receiving fludarabine as initial (n = 5) or salvage (n = 16) therapy. 12 (57%) of these patients developed herpes zoster (n = 9), herpes simplex I (n = 1) or herpes simplex II (n = 2) infections at a median of 8 (range 1-17) months following initiation of fludarabine, with 75% of these having completed therapy. All patients with herpes zoster developed severe post-herpetic neuralgia. Factors differentiating patients developing these infections included older age and low serum IgG or IgA. Based upon these prospective data, we conclude that herpes virus infections frequently occur following fludarabine treatment, necessitating aggressive patient education and new prophylactic strategies.