Human Herpesvirus 6 Infection Research Articles

Detection of human herpesvirus 6 DNA and chromosomal integration after allogeneic hematopoietic stem cell transplantation: A retrospective single center analysis.

Human herpesvirus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant morbidity and mortality. The epidemiology of HHV-6 infections and their impact on outcome after allo-HSCT were retrospectively analyzed in 689 adult allo-HSCT recipients (January 2015-December 2018). Chromosomal integration of HHV-6 (ciHHV-6) in the donor was retrospectively investigated to critically evaluate antiviral treatment strategies. HHV-6 DNA in any specimen was found in 89 patients. HHV-6 infections (encephalitis (one), gastroenteritis (44), dermatitis (two), hepatitis (one), or pneumonitis (five)) were diagnosed in 53/689 patients (7.7%). Elevated levels of HHV-6 DNA were found in 38 patients (5.5%). ciHHV-6, analyzed in patients with HHV-6 viral loads ≥104 copies/ml, was identified in four patients (10/38 patients; 10.5%). Two of those displayed copy numbers of HHV-6 ranging from ≥2×105 to 2.5×106 copies/ml (HHV-6A). Here, ciHHV-6 was integrated into donor and not into the patients' cells. In this series of allo-HSCT recipients, 10.5% of patients with blood viral loads of HHV-6 showed ciHHV-6. Screening of the donor for ciHHV-6 before initiation of antiviral therapy is recommended.

Human Herpesvirus 6 Infection and Diagnostics

Human herpesvirus 6 (HHV-6) causes primary infection in early childhood and establishes lifelong latency in its host. Reactivation of HHV-6, especially in immunosuppressed patients, has been associated with a variety of clinical complications. Diagnosis of acute HHV-6 infection has been a major challenge due to high prevalence of the virus and the difficulty in distinguishing latent infections from acute. Chromosomal integration of HHV-6 also occurs further complicating the management and diagnostics of HHV-6 disease. PCR-based methods have become the mainstay of HHV-6 diagnostics, however, interpretation of results in the context of clinical disease is of utmost importance.

Human herpesvirus 8 infection is associated with prostate cancer among IFNL4-ΔG carriers

BackgroundThe dinucleotide germline variant, rs368234815-ΔG, in the IFNL4 gene (IFNL4-ΔG) has been associated with prostate cancer among men at increased risk of sexually transmitted infections and reported to impair viral clearance. Human herpesvirus 8 (HHV-8) seropositivity has been associated with prostate cancer in Tobago.MethodsWe examined whether the association of HHV-8 with prostate cancer is IFNL4-ΔG-dependent among 728 IFNL4-ΔG-genotyped cases and 813 genotyped population-based controls from the NCI-Maryland Prostate Cancer Case-Control study. Associations between HHV-8 and prostate cancer were assessed in multivariable unconditional logistic regression models. We calculated adjusted odds ratios (OR) and stratified the analysis into men harboring the IFNL4-ΔG-variant and non-carriers (ΔG/ΔG or ΔG/TT vs. TT/TT).ResultsHHV-8 seropositivity was higher in cases than controls (11% vs. 6%) and this association was restricted to carriers of the ΔG allele (OR 2.19: 95% CI:1.38–3.48) in both African American (OR 1.96; 95% CI:1.08–3.56) and European American men (OR 2.59; 95% CI:1.20–5.56).ConclusionsHHV-8 seropositivity is associated with increased odds of prostate cancer in men harboring the IFNL4 rs368234815-ΔG variant. This study describes HHV-8 infection as a candidate prostate cancer risk factor in men with the IFNL4-ΔG genotype and supports the hypothesis that IFNL4-ΔG is a susceptibility factor that contributes to prostate cancer.

Defective Monocyte Enzymatic Function and an Inhibitory Immune Phenotype in Human Immunodeficiency Virus-Exposed Uninfected African Infants in the Era of Antiretroviral Therapy.

BackgroundHuman immunodeficiency virus-exposed uninfected (HEU) infants are a rapidly expanding population in sub-Saharan Africa and are highly susceptible to encapsulated bacterial disease in the first year of life. The mechanism of this increased risk is still poorly understood. We investigated whether human immunodeficiency virus (HIV)-exposure dysregulates HEU immunity, vaccine-antibody production, and human herpes virus amplify this effect.MethodsThirty-four HIV-infected and 44 HIV-uninfected pregnant women were recruited into the birth cohort and observed up to 6 weeks of age; and then a subsequent 43 HIV-infected and 61 HIV-uninfected mother-infant pairs were recruited into a longitudinal infant cohort at either: 5–7 to 14–15; or 14–15 to 18–23 weeks of age. We compared monocyte function, innate and adaptive immune cell phenotype, and vaccine-induced antibody responses between HEU and HIV-unexposed uninfected (HU) infants.ResultsWe demonstrate (1) altered monocyte phagosomal function and B-cell subset homeostasis and (2) lower vaccine-induced anti-Haemophilus influenzae type b (Hib) and anti-tetanus toxoid immunoglobulin G titers in HEU compared with HU infants. Human herpes virus infection was similar between HEU and HU infants.ConclusionsIn the era of antiretroviral therapy-mediated viral suppression, HIV exposure may dysregulate monocyte and B-cell function, during the vulnerable period of immune maturation. This may contribute to the high rates of invasive bacterial disease and pneumonia in HEU infants.

Disseminated Pulmonary Kaposi Sarcoma After Lung Transplantation: The Increased Risk Donor

<h3>Introduction</h3> Kaposi sarcoma (KS) is a rare complication after lung transplantation (LTx). It is caused by human herpes virus 8 (HHV-8). We report a case of primary disseminated pulmonary KS after LTx from an increased risk donor. <h3>Case Report</h3> A 66-year-old male with end-stage COPD underwent a bilateral LTx from an increased risk donor with positive HBsAb, HBcAb and Lues Ab, in November 2020. Apart from Valganciclovir (vGCV) and co-trimoxazole, entecavir and benzylpenicillin were given as prophylaxis. Routine immunosuppression included basiliximab, tacrolimus, mycophenolate mofetil (MMF) and prednisolone. vGCV prophylaxis was discontinued at 3 months (CMV-positive donor and recipient). The patient was treated effectively for acute rejection with pulse methylprednisolone in February 2021. Unfortunately, he was readmitted with dyspnea and lung function decline in April 2021. CT-scan showed bilateral consolidations and pleural thickening and the PET-scan showed an intense uptake in both lungs and pleura. Transthoracic needle biopsy showed HHV-8 positive spindle cell lesions. Subsequently, our patient developed skin lesions on his chest and in his mouth compatible with KS (biopsy-proven). In retrospect, the recipient was HHV-8 seronegative before LTx. Therefore, the diagnosis primary HHV-8 infection leading to disseminated pulmonary Kaposi sarcoma was made. Which appeared after cessation of the vGCV prophylaxis. Valganciclovir was initiated and immunosuppression was adjusted: MMF discontinued and tacrolimus switched to sirolimus (target through levels 15 µg/l). Nevertheless, KS was progressive and liposomal doxorubicin 20mg/m2 was started. Our patient deteriorated and was transferred to the ICU for intubation. Bronchoscopy revealed brown endobronchial lesions compatible with KS. The effect of the treatment could not be assessed, because the patient decided to refuse further treatment. He died soon after his decision was made. <h3>Summary</h3> Scarcity of donor organs led to the acceptance of an increased risk donor. Prophylaxis against hepatitis B and Lues was given, but after discontinuation of vGCV our patient developed a primary HHV-8 infection leading to disseminated KS and ultimately the death of our patient. HHV-8 testing of donor serum and lifelong prophylaxis might have prevented this clinical course and should be considered in recipients of increased risk donors.

Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine

Viruses are responsible for some of the most deadly human diseases, yet available vaccines and antivirals address only a fraction of the potential viral human pathogens. Here, we provide a methodology for managing human herpesvirus (HHV) infection by covalently inactivating the HHV maturational protease via a conserved, non-catalytic cysteine (C161). Using human cytomegalovirus protease (HCMV Pr) as a model, we screened a library of disulfides to identify molecules that tether to C161 and inhibit proteolysis, then elaborated hits into irreversible HCMV Pr inhibitors that exhibit broad-spectrum inhibition of other HHV Pr homologs. We further developed an optimized tool compound targeted toward HCMV Pr and used an integrative structural biology and biochemical approach to demonstrate inhibitor stabilization of HCMV Pr homodimerization, exploiting a conformational equilibrium to block proteolysis. Irreversible HCMV Pr inhibition disrupts HCMV infectivity in cells, providing proof of principle for targeting proteolysis via a non-catalytic cysteine to manage viral infection.

Rasmussen\u2019s encephalitis is characterized by relatively lower production of IFN-\u03b2 and activated cytotoxic T cell upon herpes viruses infection

BackgroundThe etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear.MethodsHHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis.ResultsAntigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-β level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE.ConclusionsCompared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

Flavonoids Target Human Herpesviruses That Infect the Nervous System: Mechanisms of Action and Therapeutic Insights.

Human herpesviruses (HHVs) are large DNA viruses with highly infectious characteristics. HHVs can induce lytic and latent infections in their host, and most of these viruses are neurotropic, with the capacity to generate severe and chronic neurological diseases of the peripheral nervous system (PNS) and central nervous system (CNS). Treatment of HHV infections based on strategies that include natural products-derived drugs is one of the most rapidly developing fields of modern medicine. Therefore, in this paper, we lend insights into the recent advances that have been achieved during the past five years in utilizing flavonoids as promising natural drugs for the treatment of HHVs infections of the nervous system such as alpha-herpesviruses (herpes simplex virus type 1, type 2, and varicella-zoster virus), beta-herpesviruses (human cytomegalovirus), and gamma-herpesviruses (Epstein–Barr virus and Kaposi sarcoma-associated herpesvirus). The neurological complications associated with infections induced by the reviewed herpesviruses are emphasized. Additionally, this work covers all possible mechanisms and pathways by which flavonoids induce promising therapeutic actions against the above-mentioned herpesviruses.

The Emergence of HHV-8 Infection among HIV-positive Individuals Residing in Bali, Indonesia

Background:&#x0D; Human herpesvirus 8 (HHV-8) is considered as the etiological agent of Kaposi’s sarcoma (KS). In people living with human immunodeficiency virus (HIV) (PLHIV), KS defines acquired immunodeficiency syndrome (AIDS). Previous study found that HIV-positive individuals were more likely to be HHV-8 seropositive than HIV-negative individuals. Reports regarding the presence of HHV-8 and HIV co-infection in Indonesia is severely limited. &#x0D; Aim:&#x0D; This study aimed to identify HHV-8 infection among HIV-positive individuals in Bali, Indonesia.&#x0D; Materials and Methods:&#x0D; Forty three plasma samples were collected from 16 antiretroviral therapy (ART) naive and 27 ART-experienced individuals residing in Buleleng Regency, Bali, Indonesia. Detection of HHV-8 antigen was performed by using ELISA method. The Fisher's Exact test and the Spearman correlation test would be used to analysed data accordingly.&#x0D; Results:&#x0D; Seven samples (7/43, 16.3%), one of ART-naive individual (1/16, 6.25%) and six of ART-experienced individuals (6/27, 22.2%), were tested positive for HHV-8 antigen. Human herpesvirus 8 infection was correlated neither to sex (p=1.000) and age (p=0.716), nor to ART status (p=0.178) and length of ART (p=0.465).&#x0D; Conclusion:&#x0D; This study indicates the emergence of HHV-8 infection among HIV-positive individuals residing in Bali, Indonesia. Sufficient diagnosis of HHV-8 should be considered for all HIV-positive individuals in order to deliver appropriate treatment. Extensive researches is suggested to be conducted in more regions of Indonesia in order to determine the magnitude of HHV-8 infection among HIV-positive individuals.

Herpesvirus Infections in KIR2DL2-Positive Multiple Sclerosis Patients: Mechanisms Triggering Autoimmunity.

In multiple sclerosis (MS), there is a possible relationship with viral infection, evidenced by clinical evidence of an implication of infectious events with disease onset and/or relapse. The aim of this research is to study how human herpesvirus (HHVs) infections might dysregulate the innate immune system and impact autoimmune responses in MS. We analyzed 100 MS relapsing remitting patients, in the remission phase, 100 healthy controls and 100 subjects with other inflammatory neurological diseases (OIND) (neuro-lupus) for their immune response to HHV infection. We evaluated NK cell response, levels of HHVs DNA, IgG and pro- and anti-inflammatory cytokines. The results demonstrated that the presence of KIR2DL2 expression on NK cells increased the susceptibility of MS patients to HHV infections. We showed an increased susceptibility mainly to EBV and HHV-6 infections in MS patients carrying the KIR2DL2 receptor and HLA-C1 ligand. The highest HHV-6 viral load was observed in MS patients, with an increased percentage of subjects positive for IgG against HHV-6 in KIR2DL2-positive MS and OIND subjects compared to controls. MS and OIND patients showed the highest levels of IL-8, IL-12p70, IL-10 and TNF-alpha in comparison with control subjects. Interestingly, MS and OIND patients showed similar levels of IL-8, while MS patients presented higher IL-12p70, TNF-alpha and IL-10 levels in comparison with OIND patients. We can hypothesize that HHVs’ reactivation, by inducing immune activation via also molecular mimicry, may have the ability to induce autoimmunity and cause tissue damage and consequent MS lesion development.

Human herpesvirus 6 infection as a trigger of multiple sclerosis: an update of recent literature

BackgroundThis is an update on the existing evidence regarding a relationship between infection with human herpesvirus 6 (HHV-6) and multiple sclerosis (MS) in order to contribute on the attempt to define the nature and strength of that relationship.ResultsStudy quality was assessed using the criteria proposed by Moore and Wolfson and by the classification criteria used by the Canadian Task Force on the Periodic Health Examination. Studies were categorized both by experimental technique and by quality (high [A], intermediate [B], and low [C]) as determined by the Moore and Wolfson criteria. Overall, 27 (90%) of 30 studies, 18 (86%) of which were classified as A quality, reached a statistically significant result. According to the Canadian Task Force classification, all studies were categorized as evidence of qualityII-1. Limitations of the available experimental techniques and perspectives for future research are discussed.ConclusionsThe current review continues to emphasize the need for further, objective, evidence-based examination of the relationship between HHV-6 infection and multiple sclerosis.

Use of liquid chromatography-tandem mass spectrometry for foscarnet quantification in human serum and cerebrospinal fluid.

Foscarnet (FCV) is used to treat cytomegalovirus, human herpesvirus, and human immunodeficiency virus infections. It is a low-molecular-weight compound containing carboxylate and phosphate groups. There are no reports on the use of liquid chromatography-tandem mass spectrometry (LC/MS/MS) to analyze FCV via bioanalysis. In the present study, we developed the ion-pair LC/MS/MS method to analyze FCV in human serum and cerebrospinal fluid (CSF). FCV was extracted from human serum and CSF by weak anion exchange (WAX) solid-phase extraction. The LC/MS/MS systems were coated with 0.1% phosphoric acid in methanol to avoid nonspecific absorption. FCV was detected using ion-pair LC/MS/MS with dibutylammonium acetate. Selected reaction monitoring transition of FCV in the negative ion mode was selected at m/z 125.1 → 62.9. FCV was selectively detected in human serum and CSF, and the liner range was 5-1000 μM (R2 = 0.99). The intraday and interday accuracy and precision were within ±15%. FCV was constantly extracted from human serum and CSF by WAX solid-phase extraction (recovery ratio = 76.0-77.9%). No matrix effect was observed. A robust LC/MS/MS method to analyze FCV was successfully developed. FCV was selectively measured using LC/MS/MS in very low extract volumes (20 μL). The method will be useful in evaluating the FCV level in human serum and CSF.

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention.

Introduction: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. Results: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3–12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. Conclusion: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

Human herpesvirus infections and circulating microvesicles expressing galectin-3 binding protein in patients with systemic lupus erythematosus.

Circulating microvesicles (MVs) expressing the type 1 interferon-inducible protein galectin-3 binding protein (G3BP) are potentially major sources of autoantigens in systemic lupus erythematosus (SLE). In this study, we explore if plasma concentrations of G3BP-expressing MVs correlate with signs of various active human herpesvirus (HHV) infections in SLE patients, suggesting a virus-induced mechanism for the generation of these vesicles. In 49 SLE patients, the plasma levels of immunoglobulin G (IgG) against cytomegalovirus (CMV) pp52, Epstein-Barr virus (EBV) early antigen diffuse (EA/D), and HHV6 p41 were measured by ELISAs and used as humoral markers of ongoing/recently active viral infection. MVs in platelet-poor plasma were quantified and characterised by flow cytometry, with regard to the binding of Annexin V (AnxV) and the expression of G3BP. Spearman's rho and the Wilcoxon rank-sum test were applied for associative evaluation of virus serology with MV subsets, and clinical and demographic data. The CMV pp52-directed antibodies correlated positively with the high G3BP-expressing MVs; either low (rho=0.4, p-value=0.005) or high (rho=0.37, p-value=0.01) in AnxV-expression. Furthermore, these MV subsets were higher in individuals with high and low IgG levels against CMV pp52 and EBV EA/D, respectively, relative to subjects with low and high IgG levels against these HHV antigens. Importantly, none of the associations were explained by immunosuppressants or antimalarials. Ongoing/recently active CMV infection is associated with circulating MVs expressing G3BP in SLE patients, supporting a link between specific viral infections and potentially pathogenic MVs in SLE.

Markers of Epstein-Barr virus and Human Herpesvirus-6 infection and multiple sclerosis clinical progression

BackgroundInfections with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) have been implicated in multiple sclerosis (MS) onset but little work has studied their relationships in early disease. ObjectiveEvaluate associations between markers of EBV and HHV-6 infection/reactivation and MS conversion, relapse and EDSS/MSSS amongst 205 CIS participants with EBV/HHV-6 data followed over 5 years. MethodBaseline serological and viral load measures of EBV and HHV-6 exposure/reactivation were measured and infectious mononucleosis (IM) history recorded. Conversion to MS and relapses were assessed annually, and EDSS/MSSS measured at 5-year review. Determinants of MS conversion and relapse assessed by Cox regression, and disability progression by linear regression. ResultsIM history showed a strong positive trend with higher relapse risk (aHR=1.45,95%CI=0.97–2.16) but was not associated with MS conversion (aHR=0.92,95%CI=0.57–1.48). Anti-HHV-6 IgG titre>40 also showed strong positive trends with higher relapse (aHR=1.61,95%CI=0.99–2.63) and MS conversion risks (aHR=1.48,95%CI=0.89–2.46). Anti-HHV-6 IgG titre≥640 was significantly associated with higher MSSS (0.15(95%CI=0.00,0.30) and also showed a strong positive trend with higher EDSS 0.10(95%CI=-0.02,0.21). HHV-6 DNA detection showed strong positive trends with 83%(95%CI=-6–357) and 77%(95%CI=-4–328) higher MS conversion and relapse risk. Anti-EBV-EA-D IgG titre was associated with a lower annualised disability progression by EDSS (ptrend=0.037) and also showed strong positive trend with higher MSSS (ptrend=0.053). No associations were seen for other serological or viral load markers. ConclusionOverall, our data provides evidence that higher HHV-6 IgG was associated with increased risk of MS conversion and relapse but of borderline significance, and greater annualised disability progression, while that for EBV was more limited.

Valganciclovir as Add-On Therapy Modifies the Frequency of NK and NKT Cell Subpopulations in Disseminated Kaposi Sarcoma Patients.

Simple SummaryKaposi sarcoma is one disease that develops in people living with HIV with severe immunosuppression and impacts morbidity and associated mortality. This disease is currently treated with antiretroviral therapy and chemotherapy agents that can further contribute to immunosuppression in patients. Thus, searching for new therapies to induce a robust immune system activation in these patients is necessary. Herein, the frequency and phenotype of natural killer subpopulation cells in people living with HIV with Kaposi sarcoma were evaluated. After KS diagnosis, patients started antiretroviral therapy or valganciclovir plus antiretroviral therapy. Results showed that in patients treated with valganciclovir plus antiretroviral therapy, the expression of CD57 and CD27 proteins on natural killer cells was regulated, enhancing the immune response of the study cohort. This finding contributes to understanding more about the immune response of people living with HIV with Kaposi sarcoma.Human herpesvirus-8 infection (HHV-8) is the causative agent of Kaposi sarcoma (KS) and is highly prevalent among people living with HIV (KS/HIV). It has been reported that valganciclovir (VGC) reduces HHV-8 replication in KS/HIV patients. However, currently it is unclear if VGC modifies the frequency and induces changes in markers of immune regulation of immune cells necessary to eliminate HHV8-infected cells, such as Natural Killer (NK) and NK T cells (NKT). This study evaluated the effect of VGC used as antiviral HHV8 therapy in KS patients on the frequency of NK and NKT subpopulations based on the CD27 and CD57 expression, and the immunosenescence markers, PD-1 and KLRG1. Twenty KS/HIV patients were followed-up at baseline (W0), 4 (W4), and 12 weeks (W12) of the study protocol. Among them, 10 patients received a conventional treatment scheme (CT), solely antiretroviral therapy (ART), and 10 patients received a modified treatment regime (MT), including VGC plus ART. In both groups, bleomycin/vincristine was administrated according to the treating physician’s decision. The soluble levels of IL-15, PD-L1, PD-L2, and E-cadherin were quantified across the follow-up. Our results showed that the higher IL-15 levels and lower NK frequencies cells in KS/HIV patients reach almost normal values with both treatments regimes at W12. CD27+ NK and NKT cell frequencies increased since W4 on KS/HIV patients with MT. Furthermore, PD-1 expression decreased while KLRG1 increased on NK and NKT subpopulations at W12, and it is accompanied by increased PD-L1 plasma level since W4. Our study highlights the disruption of NK and NKT subpopulations in patients with KS/HIV and explores VGC treatment’s contribution to immune reconstitution during the first weeks of treatment.

First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature

BackgroundDedicator of cytokinesis 2 (DOCK2) deficiency is an inborn error of immunity characterized by cellular and humoral immunological abnormalities leading to early-onset infections.Case presentationWe reported a novel case of a 27 months old girl presenting with recurrent pneumonia and a history of skeletal tuberculosis at the age of 19-month-old. Her immunological workup revealed persistent lymphopenia and low CD4 + T cell count along with elevated levels of CD19 +, CD20 +, CD16 +, and CD56 + cells. Furthermore, she had a high level of immunoglobulin (Ig) E and a slightly reduced IgM level with a non-protective antibody titer against diphtheria. The whole-exome sequencing (WES) analysis identified a homozygous frameshift deletion mutation (c.1512delG, p.I505Sfs*28) in exon 16 of the DOCK2 gene. We also conducted electronic searches in PubMed, Web of Science, and Scopus databases and reviewed the articles reporting patients with DOCK2 deficiency. The literature search yielded 14 DOCK2-deficient patients suffering from both cellular and humoral immune defects leading to early-onset infections, particularly human herpesvirus (HHV) infection.ConclusionDOCK2 deficiency should be considered in the context of severe or unusual early-onset infections, especially HHV infections, in a patient with a probable clinical diagnosis of combined immunodeficiency. We also recommended that DOCK2-deficient patients might benefit from T-cell receptor excision circle (TREC) assay as part of the routine newborn screening program.

Human Herpesvirus 6 Meningitis in a Neonatal Case

Incidence of human herpesvirus-6 (HHV-6) infection in the neonatal period has been reported in few cases. HHV-6, commonly responsible for roseola, is known to establish infection during infancy and early childhood. A 14-day-old neonate, presented with a fever of 38.3℃, primarily due to an HHV-6 infection, was admitted to our neonatal intensive care unit. A polymerase chain reaction (PCR) of his cerebrospinal fluid was positive for HHV-6. Additionally, serology for HHV-6 PCR was positive. We believe that HHV-6 can cause infection in febrile newborn infants.

Synthesis and biological evaluation of novel rhodanine-based structures with antiviral activity towards HHV-6 virus

An increased awareness of diseases associated with Human herpesvirus 6 (HHV-6) infection or reactivation has resulted in a growing interest in the evaluation of the best treatment options available for the clinical management of HHV-6 disease. However, no compound has yet been approved exclusively for HHV-6 infection treatment. For this reason, the identification of anti-HHV6 compounds provides a valuable opportunity for developing efficient antiviral therapies. A possible target for antiviral drugs is the virus-cell fusion step. In this study, we synthetized potential fusion intermediates inhibitors based on the rhodanine structure. The obtained derivatives were tested for cytotoxicity and for antiviral activity in human cells infected with HHV6. Level of infection was monitored by viral DNA quantification at different time points up to 7 days post infection. Among the synthetized derivatives, 9e showed a significative inhibitory effect on viral replication that lasted over 7 days, probably attributable to the particular combination of hydrophilic and hydrophobic substituents to the rhodanine moiety. Our results support the use of these amphipathic fusion inhibitors for the treatment of HHV-6 infections.

EFFECT OF HUMAN HERPES VIRUS REACTIVATION ON SYSTEMIC CYTOKINE PRODUCTION IN PATIENTS WITH BEHCET’S DISEASE AND UVEITIS

Behcet’s disease (BD) is a systemic autoinflammatory-autoimmune disease (chronic systemic vasculitis) of unknown etiology, almost 70% of patients develop uveitis. BD pathogenesis is complex, human herpesviruses (HHV) play an important role among infectious trigger factors. Ability of herpesviruses to modulate cytokine production and evade host’s immune response is known.Aim of the study was to assess the effect of Herpes simplex virus type 1, Herpes simplex virus type 2, Cytomegalovirus, Epstein-Barr virus on systemic levels of chemokines, pro- and anti-inflammatory cytokines in BD with and without uveitis. Serum samples were collected from 116 BD patients chronically infected with HHV and examined in ELISA-test for markers of HHV reactivation (IgG-antibodies to immediate early HSV antigens 1, 2 and CMV, early EBV antigen). Concentration of IL-1β, IFNγ, MCP-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13, IL-18, TNFα, GMCSF, Eotaxin, GRO-α, IP-10, MIP-1α, MIP-1β, SDF-1α, RANTES detected in multiplex analysis. TGF-β1, TGF-β2 were measured in ELISA-test. Depending on presence and activity of uveitis 3 groups of patients with BD were identified: group 1 – active uveitis, group 2 – remission of uveitis, group 3 – BD without ocular manifestations. After serological study 2 subgroups were highlighted in each group: a) patients with antibody markers of reactivation of at least one HHV, b) patients chronically infected with HHV, without serological signs of reactivation. Mean level and detection rate of cytokines and chemokines in patients with active uveitis (1a, 1b) and in remission (2a, 2b) were compared with patients without eye damage (3a, 3b). Chronic HHV infection (subgroup “b”) was compared with reactivation (subgroup “a”). A significant increase of MCP-1/ CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, IP-10, SDF-1α chemokines in serum, as well as IFNγ, TGF-β1, and TGF-β2 was observed in patients with uveitis (regardless of their activity) and HHV reactivation compared to patients without uveitis. Our data indicate that systemic production of cytokines and chemokines in BD patients and uveitis could be affected by the activity of chronic herpesvirus infections, and the greatest changes are related to chemokines.