Human Herpesvirus 6 DNA 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.

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.

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.

Herpes Virus Reactivation in Lymphoma Patients During and After Autologous Hematopoietic Stem Cell Transplantation

Aim. To assess the detection rate of human herpes virus DNA (of cytomegalovirus, herpes simplex virus types 1 and 2 [HSV-1/2], human herpes virus type 6 [HHV-6], and Epstein-Barr virus) in different biological environments at different stages of autologous hematopoietic stem cell transplantation (auto-HSCT) as well as the effect of immune factors on reactivation of viruses under study. Materials &amp; Methods. From 2019 to 2021 the study enrolled 87 lymphoma patients during and after auto-HSCT. Virological monitoring was performed on biological fluids (blood, saliva, urine, etc.) prior to conditioning regimen on Day 0 as well as on Day +5 and Day +10 after auto-HSCT. On these days (Day 0, Day +5, and Day +10) the immune factors (IgM, IgG, and IgA levels and pattern of lymphocyte subpopulation in peripheral blood) in 15 % (14/87) of patients were assessed in terms of their effect on herpes virus reactivation. Results. The overall rate of viral DNA detection increased from 26 % (26/87) to 42 % (37/87) of cases in the period of granulocytopoietic recovery. The most frequent were HHV-6 and HSV-1/2 reactivations reported in 23 % (20/87) and 16 % (14/87) of cases, respectively. The median B-lymphocyte proportion in peripheral blood of patients with herpes virus reactivation was 0.26 %, whereas in patients without reactivation it was 6.7 % (p = 0.019). The median absolute B-lymphocyte count in the cohort of patients with detected viral DNAs was 0.001 &lt;sup&gt;x&lt;/sup&gt; 10&lt;sup&gt;9&lt;/sup&gt;/L, whereas in patients without them it was 0.098 &lt;sup&gt;x&lt;/sup&gt; 10&lt;sup&gt;9&lt;/sup&gt;/L (p = 0.026). Conclusion. A high rate of herpes virus DNA detection in lymphoma patients after auto-HSCT affected neither transplant engraftment nor transplantation mortality. Immune predictors of virus infection reactivation were the decreasing proportion of B-cells in the total lymphocyte count and the absolute B-lymphocyte count in the peripheral blood prior to auto-HSCT.

Herpesviruses in patients after renal transplantation

To estimate graft function after kidney transplantation during active herpesviruses or superinfection Materials and methods. The study included 32 patients (men 21, women 11) with end-stage chronic kidney disease. The median age was 43 years. Cytomegalovirus (CMV), EpsteinBarr virus (EBV) and human herpes virus 6 (HHV-6) DNAs were screened by RT-PCR in the donor's transplant biopsy, and recipients peripheral blood and urine after kidney transplantation (KT) on 0, 1, 2, 4, 6, 12 months. Antiviral antibodies (IgM and IgG) were also screened by Enzyme-linked immunoassay analysis (ELISA) along with PCR. The 500 or less copies of viral DNA per 105 nuclear cells or 1 ml of urine was considered as low, more than 1000 copies high. On the first month after KT CMV DNA was detected in 50% of pts., EBV DNA in 40% and HHV-6 DNA in 33%. During first year after KT two or three viruses simultaneously were found in 12 recipients: CMV, EBV, and HHV-6 were detected in 5 recipients; CMV and EBV in 4 patients; CMV and HHV-6 in 2 pts; EBV and HHV-6 in 1 pt. Graft dysfunction was observed in 9 patients with a high concentration of viral DNA of one, two or three viruses simultaneously. An upraise of the concentration of virus DNA (CMV, EBV and HHV 6) was detected primarily in the urine, while in the blood its concentration was less than 500 cop or undetectable. Renal dysfunction was not observed on the background of low concentrations of viral DNA in urine and blood. However, with an increase of DNA concentration, an impaired graft function in 8 of 12 patients appeared. Low viral DNA level proved to be a background for another virus activation or bacterial/fungal superinfection. Graft dysfunction occurs at high viral DNA levels detection during mono-or superinfection. Low viral load can serve as a background for another virus activation and/or bacterial/fungal superinfection.

Serum Soluble OX40 as a Diagnostic and Prognostic Biomarker for Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction commonly associated with the reactivation of human herpesvirus 6 (HHV-6). There are currently no adequate biomarkers for the early diagnosis and detection of DIHS/DRESS. Notably, OX40 (CD134) has an important role in allergic inflammation and functions as a cellular receptor for HHV-6 entry. We previously reported that the membrane-bound form of OX40 in CD4+ T cells was upregulated in DIHS/DRESS. We sought to investigate the clinical significance of serum soluble OX40 (sOX40) in DIHS/DRESS. Serum sOX40 levels in patients with DIHS/DRESS (n= 39), maculopapular exanthema/erythema multiforme (n= 17), Stevens-Johnson syndrome/toxic epidermal necrolysis (n= 13), or autoimmune bullous diseases (n= 5), and levels in healthy volunteers (n= 5) were examined by enzyme-linked immunosorbent assay. Copy numbers of HHV-6, HHV-7, and cytomegalovirus in peripheral blood mononuclear cells were quantified using real-time PCR. Serum sOX40 levels in patients with DIHS/DRESS in the acute stage were elevated in parallel with high OX40 expression on CD4+ T cells. Serum sOX40 levels were significantly positively correlated with disease severity and serum levels of thymus and activation-regulated chemokine, IL-5, and IL-10. Human herpesvirus 6-positive patients had higher sOX40 levels than did HHV-6-negative patients, and serum sOX40 levels were correlated with HHV-6 DNA loads. Serum sOX40 levels can be a useful diagnostic marker for DIHS/DRESS that reflect disease severity. Elevated serum sOX40 levels also predict HHV-6 reactivation in patients with DIHS/DRESS.

Molecular Detection and Genotyping of Human Herpes Virus 8 in a sample of Iraqi Blood Donors

Human herpes virus-8 (HHV-8) infection has increased recently in Arabic countries. HHV-8 in healthy persons does not necessarily cause life-threatening infection, and however, it causes a more severe infection among immunocompromised patients. The distribution of HHV-8 genotypes varies according to ethnicity and depends on the geographic region prior rapid development of global travel. A cross sectional prospective study included a hundred healthy blood donor samples with a mean age of (36.60±10.381), 81% were positive for molecular detection of HHV-8 DNA. PCR results for HHV-8 were strongly related with risk factors such as the number of sexual relations, previous surgeries, blood transfusion, dental operation, and the number of blood donations. In this study, genotypes (A, B, C and D) were detected, largely associated with blood donors residences and distributed to areas of Iraq through a map. Genotype A comprised 28 (34.6%) of blood donors and for genotype C it was 16 (19.8%) and both genotypes were found to be the predominant genotypes, followed by genotype B of 7 (8.7%) and D of 2 (2.5%), the latter is included into Mixed genotypes of 8 (9.9%), whereas, 22 (27.2%) were undetermined genotypes. Efforts should focus on these findings, which may indicate that Iraq is an endemic region of HHV-8 infection.

Analysis of autoantibody spectrum and human herpesvirus 6 in adult patients with ‘early’ versus ‘late’ diagnosis of ‘possible limbic encephalitis’

New onset temporal seizures are increasingly encountered in adult patients. Many of those fulfill diagnostic criteria for possible or definite limbic encephalitis (LE). LE is associated with autoantibodies (autoABs) against neuronal surface structures (‘neuronal’ autoABs), ‘onconeuronal’ or GAD65. AutoABs can emerge in a paraneoplastic setting. However, by far not all patients with possible/definite LE have an oncological history. AutoABs have also found to arise in the context of viral encephalitis. Rare associations between autoAB-positive LE and human herpes virus 6 (HHV-6) infection have been as well reported. Our present analysis was dedicated to learn about potentially different autoAB spectra and HHV-6 detection rates in adult-onset temporal seizure patients with possible LE and largely different time spans between first seizure events and referral to a tertiary epileptological center due to pharmacoresistent seizures. We scrutinized serum/CSF samples obtained from adults with ‘early diagnosis’ of possible LE (≤ 30 months after first seizure event; n = 94) versus a patient group with ‘late diagnosis’ of possible LE (≥ 97 months; n = 45) for the presence of autoABs and HHV-6 DNA. AutoABs were detected in CSF and/or serum samples (n = 20) in 21.3 % of the early diagnosis patients with the highest abundance of anti-LGI1 (n = 8), significantly more frequent than in the late diagnosis group (autoAB positive: n = 4 (8.9 %); *p < 0.05, Fisher’s Exact Test). Quantitative PCR revealed viral HHV-6 DNA in only one serum sample of the early diagnosis cohort but no evidence in corresponding CSF samples or in any sample of the late diagnosis group. The present data demonstrate a higher incidence of distinct autoABs in adults with early diagnosis of possible LE. The distinct spectra of autoABs have to be taken into account in the differential diagnosis of possible LE patients with short versus more sustained duration of temporal seizure activity.

Human Herpesviruses Increase the Severity of Hepatitis.

Simple SummaryMore than 300 million people worldwide suffer from hepatitis B or hepatitis C and more than 1 million people die each year from cirrhosis and liver cancer. In some cases, the nature of hepatitis remains unclear. The purpose of this research was to assess the prevalence of human herpesviruses (cytomegalovirus, Epstein–Barr virus, and herpesvirus type 6) in patients with hepatitis, and to examine their effect on the disease severity. In the clinical materials of 377 patients with acute or chronic hepatitis, DNA of these three herpesviruses was detected in the blood in 13.5% of patients with viral hepatitis B or C and in 10.1% of patients with hepatitis of unspecified etiology. The cirrhosis was diagnosed in patients with herpesviruses 3 times more often than in patients without them. In patients with hepatitis C, the incidence of herpesviruses was higher in the tissue samples of liver biopsies (38.7%) than in the blood. Clinical and virological indicators of hepatitis were considerably higher in the patients with coinfection. Since in patients with hepatitis the presence of herpesviruses is associated with a more severe course of the disease, the detection, and herpesvirus DNA monitoring will help to adjust the course of therapy.Acute and chronic liver diseases are a major global public health problem; nevertheless, the etiology of 12–30% of cases remains obscure. The purpose of this research was to study the incidence of human herpesviruses (HHVs) cytomegalovirus, Epstein–Barr virus (EBV), and HHV-6 in patients with hepatitis and to examine the effect of HHV on the disease severity. We studied the clinical materials of 259 patients with hepatitis treated in Infectious Clinic n.1 (Moscow) and the archived materials of 118 patients with hepatitis C. HHV DNA was detected in the whole blood in 13.5% of patients with hepatitis B or C and in 10.1% of patients with hepatitis of unspecified etiology. EBV demonstrated the highest incidence (58.1%). Cirrhosis was diagnosed in 50% of patients with HHV and in 15.6% of patients without HHV. In patients with hepatitis C, the frequency of HHV was higher in liver biopsy (38.7%) compared to blood. The clinical and virological indicators of hepatitis were considerably higher in patients with coinfection. Conclusion: HHV detected in patients with viral hepatitis has been associated with a significant effect on the severity of the disease, and we suggest monitoring HHV DNA in patients with severe hepatitis and/or poor response to antiviral drugs.

The risk of systemic lupus erythematosus associated with Human Herpesvirus 8 (HHV-8) infection: A systematic review and meta-analysis

IntroductionSeveral organs are involved in systemic lupus erythematosus (SLE) disorder. The possible role of Herpesviruses have also been extensively in the development of SLE. To understand the more information about the epidemiology association between Human Herpesvirus 8 (HHV-8) and SLE, we designed this study with the purpose of a systematic review and meta-analysis of the seropositivity rate and the presence of HHV-8 DNA among SLE patients in comparison to controls. MethodsA systematic literature search was carried out in the Web of Science, PubMed, Scopus and Embase databases. The search was limited to the papers that were published by international authors to end of 31 October 2019. Data analysis were performed by Comprehensive Meta-Analysis Software Version 2.2 (Biostat, USA). ResultsThe positive rate of HHV-8 DNA was 4.1% and 1% for the SLE and the control group, respectively. The overall prevalence of HHV-8 antibodies was estimated at 13% and 2.9% among the SLE and the control group, respectively. The pooled odds ratios (OR) from these studies was 8.06 and 4.52 based on molecular and serological methods and representing a significant association between risk of HHV-8 and SLE than in the healthy controls. According to Q statistic and the I2 index, heterogeneity was not significant for the SLE and the control group. ConclusionIn conclusion, HHV-8 prevalence was significantly high in SLE patients than healthy group based on two detection methods. Therefore, our finding suggested the possible role between HHV-8 and the development of lupus.

Human herpesvirus 6 and central nervous system disease in oncology patients: A retrospective case series and literature review.

Human herpesvirus 6 (HHV-6) can reactivate with immunosuppression and cause central nervous system (CNS) dysfunction. Much of the literature describes cases after hematopoietic stem cell transplantation (HSCT), ranging from encephalitis to a post-transplant acute limbic encephalitis syndrome (PALE). Outside of HSCT, studies of HHV-6 encephalitis are limited to case reports. This study was designed to review HHV-6 CNS infection, and evaluate all patients admitted to MD Anderson Cancer Center between March 2016 and December 2018 with detectable HHV-6 DNA in the cerebrospinal fluid (CSF). Patients with HHV-6 DNA detected in the CSF using the Viracor or Biofire® Meningitis Encephalitis Panel platforms and no other identified etiology were identified and demographic features, known risk factors, imaging findings, CSF analysis, treatments and patient outcomes were extracted from medical records. 725 patients underwent HHV-6 testing during the study timeframe, with 19 cases (2.6 %) of HHV-6 mediated CNS disease identified. Most patients, 13/19 (68 %), had undergone HSCT with median time to presentation of 31 days after transplant. Survival at 240 days after transplant was 62 %. CSF had lymphocyte predominance and nearly all patients had peripheral lymphopenia. Other at risk populations identified included patients who received chimeric antigen receptor (CAR) T-cell therapy and biologic immunotherapy. Notable discordance among testing platforms was found in 5/9 (55 %) instances. In addition to HSCT patients, HHV-6 reactivation leading to CNS disease also occurs in settings such as following adoptive T cell therapy or biologic immunotherapy. Significant diagnostic discordance exists between testing platforms.

Human herpesvirus 6 reactivation in unmanipulated haploidentical hematopoietic stem cell transplantation predicts the occurrence of grade II to IV acute graft-versus-host disease.

Human herpesvirus 6 (HHV-6) reactivation is relatively common after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the incidence of HHV-6 reactivation and the clinical outcomes following unmanipulated haploidentical HSCT (haplo-HSCT) remain unknown. We prospectively monitored blood HHV-6 DNA using real-time quantitative polymerase chain reaction weekly until day 100 post unmanipulated haplo-HSCT in patients with hematological malignancies. From November 2016 to March 2017, 102 patients (58 male and 44 female, median age 25(2-58) years old) were enrolled. Within 100days post-transplantation, 27 patients (27/136, 19.9%) developed HHV-6 viremia with a median onset time of 14 (7-98) days. The cumulative incidence of HHV-6 reactivation on day 100 post-HSCT was 25.5±4.3% in haplo-HSCT. The median HHV-6 copy number was 1.45×103 (5.48×102 -2.00×104 ) copies/ml. The HHV-6 viremia duration time was 7days in 23 patients, 14days in one patient and 21days in one patient. In multivariate analysis, prior HHV-6 reactivation was an independent risk factor for grade 2-4 graft-versus-host disease (GVHD). But it did not influence the overall survival (OS)(HR 1.624, 95%CI 0.768-3.432, P=.204), disease-free survival (DFS) (HR 1.640, 95%CI 0.799-3.367, P=.177) and non-relapse mortality (NRM) (HR 1.644, 95%CI 0.670-4.038, P=.278). The reactivation of HHV-6 after unmanipulated haploidentical transplantation predicts the occurrence of grade 2-4 a-GVHD, but it may not influence the overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM).

Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts.

ObjectiveThe aim of this study was to analyze the clinical, radiologic, and biological features associated with human herpesvirus 6 (HHV-6) encephalitis in immunocompetent and immunocompromised hosts to establish which clinical settings should prompt HHV-6 testing.MethodsWe performed a retrospective research in the virology database of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) for all patients who tested positive for HHV-6 DNA in the CSF and/or in blood from January 2008 to September 2018 and separately assessed the number of patients meeting the criteria for HHV-6 encephalitis in the group of immunocompetent and immunocompromised hosts.ResultsOf the 926 patients tested for HHV-6 during the period of interest, 45 met the study criteria. Among immunocompetent hosts (n = 17), HHV-6 encephalitis was diagnosed to 4 infants or children presenting with seizures or mild encephalopathy during primary HHV-6 infection (CSF/blood replication ratio <<1 in all cases). Among immunocompromised hosts (n = 28), HHV-6 encephalitis was diagnosed to 7 adolescents/adults with hematologic conditions presenting with altered mental status (7/7), seizures (3/7), vigilance impairment (3/7), behavioral changes (2/7), hyponatremia (2/7), and anterograde amnesia (1/7). Initial brain MRI was altered only in 2 patients, but 6 of the 7 had a CSF/blood replication ratio >1.ConclusionsThe detection of a CSF/blood replication ratio >1 represented a specific feature of immunocompromised patients with HHV-6 encephalitis and could be of special help to establish a diagnosis of HHV-6 encephalitis in hematopoietic stem cell transplant recipients lacking radiologic evidence of limbic involvement.

Reactivation and Persistence of Human Herpesvirus-8 Infection in B Cells and Monocytes by Th-1 Cytokines Increased in Kaposi's Sarcoma

AbstractPatients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load higher than patients without KS and present a CD8+ T-cell activation with production of Th1-type cytokines both in tissues and peripheral blood mononuclear cells (PBMC). Because in tissues of KS patients detection of inflammatory cytokines (IC) can precede detection of HHV-8 DNA and because signs of immunoactivation and/or dysregulation can precede KS development, we investigated the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell populations from 45 patients with KS and 45 patients at risk of KS were analyzed for HHV-8 DNA and/or gene expression and for cell survival, growth, and phenotype before or after culture with or without the IC increased in KS. The results indicate that PBMC that are polymerase chain reaction (PCR)-positive at day 0 generally loose the virus upon culture. However, the presence of IC maintains HHV-8 DNA load in cultured cells. In addition, IC increase viral load to detectable levels in PBMC from serologically positive patients that were PCR-negative before culture. γ Interferon is sufficient for these effects, whereas tumor necrosis factor and interleukin-6 have little or no activity. The increase of HHV-8 DNA by IC is observed after short-term (7 days) or long-term (28 days) culture of the cells and occurs in one or both of the two circulating cell types that are infected in vivo: B cells and monocytes. In both cases it is associated with lytic gene expression, suggesting that virus reactivation is one of the most likely mechanisms for the effect of IC on virus load. However, IC have also effects on the cells target of HHV-8 infection, because they increase B-cell survival and induce the growth and differentiation of monocytes into KS-like spindle cells with markers of endothelial macrophages. Because cells with markers of endothelial macrophages are present in blood and lesions from KS patients and are infected by HHV-8, these data may explain the high HHV-8 load associated with KS development and suggest that infected monocytes may carry the virus to tissues, transmit the infection, or differentiate in loco in spindle cells with endothelial macrophage markers.

Lack of serologic association of human herpesvirus-8 (KSHV) in patients with monoclonal gammopathy of undetermined significance with and without progression to multiple myeloma

AbstractBecause human herpesvirus-8 (HHV-8) DNA has been found in multiple myeloma (MM) patients by polymerase chain reaction, it was suggested that HHV-8 may play a role in the transformation of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore, 362 MGUS sera with and without progression to MM were tested for IgG antibody to HHV-8. Only 7.8% of the MGUS sera contained HHV-8 antibody to lytic proteins, and IgG antibody to HHV-8 latent antigen was even lower than lytic antibody (2.9%). No differences were observed in the distribution of antibody to HHV-8 in sera from MGUS patients who progressed to MM. The seroprevalences of HHV-8 in MGUS (7.8%), MM (5.4%), and healthy donors (5.9%) were similar, thus arguing for the lack of epidemiologic evidence of HHV-8 participation in the pathogenesis of MM. MGUS patients were immune competent in response to Epstein-Barr virus (EBV) infection because 97% contained antibody to EBV virus capsid antigen.

Human Herpesvirus 7 Induces CD4+ T-Cell Death by Two Distinct Mechanisms: Necrotic Lysis in Productively Infected Cells and Apoptosis in Uninfected or Nonproductively Infected Cells

AbstractWe have investigated the cytopathic effects induced by the T-lymphotropic human herpesvirus 7 (HHV-7) on the CD4+ T-lymphoblastoid SupT1 cell line and primary CD4+ T lymphocytes. Acute in vitro HHV-7 infection induced (1) the formation of giant multinucleated syncytia, which eventually underwent necrotic lysis, and (2) single-cell apoptosis. Both cytopathic effects increased with the progression of infection and were blocked by phosphonoformic acid, a specific inhibitor of herpetic DNA polymerase. Using electron microscopy analysis of various samples, we found that all syncytia contained large amounts of virions and that most of them exhibited clear evidence of necrosis, whereas apoptosis was predominantly observed in single cells. Although empty viral capsids could be identified in the cytoplasm of approximately 25% of single cells exhibiting an apoptotic morphology, mature virions were hardly observed in these cells. In both coculture and cell-free HHV-7 infection experiments, a significant correlation was observed between the degree of single-cell apoptosis, evaluated by quantitative flow cytometry after propidium iodide staining, and the decrease in the total number of viable cells. Moreover, in cell-free infection experiments, apoptosis showed a positive correlation also with the viral load, monitored by quantitative HHV-7 DNA polymerase chain reaction. Thus, it appears that apoptosis occurred predominantly in uninfected bystander cells but not in productively HHV-7–infected cells.

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT). In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed. A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584copies/mL vs 587copies/mL; P<.0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P=1.00, Fisher's exact test) or oral mucosal GVHD (P=.71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva. Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.

Inherited chromosomally integrated human herpesvirus 6 and autoimmune connective tissue diseases.

Entire genome of human herpesvirus 6 (HHV-6) that integrates into human chromosomes is called chromosomally integrated HHV-6 (ciHHV-6). Several viral infections have been suggested to be involved in autoimmune connective tissue diseases (CTDs). Reactivated HHV-6 from the integrated viral genome can induce immune responses against the virus. Thus, it is plausible that ciHHV-6 is associated with autoimmune CTDs. We sought to determine whether the prevalence of ciHHV-6 was significantly higher in patients with autoimmune CTDs than in a healthy population. A total of 846 peripheral blood samples collected from autoimmune CTD patients were analyzed. Since there was a large number of samples, they were pooled into 24 samples per group. Copy numbers of HHV-6 DNA were measured by real-time PCR. The threshold level for distinguishing between ciHHV-6 and active viral infection and the reliability of pooled DNA analysis were examined as initial validation experiments. The threshold level was 1.6 × 10^6 copy/mL in whole blood. The reliability of pooled DNA analysis to identify one ciHHV-6 sample among 23 HHV-6 DNA-negative samples was high. No HHV-6 DNA was detected in any of the pooled DNA samples collected from the patients. The probability of the present study including the 846 autoimmune CTD patient's samples was statistically not different with a healthy Japanese population which was 0.2 % or 0.6 %. There was no significant difference in the prevalence of ciHHV-6 between a healthy population and patients with autoimmune CTDs.

Human herpesvirus‐8–positive primary effusion lymphoma in HIV‐negative patients: Single institution case series with a multidisciplinary characterization

Primary effusion lymphoma (PEL) is a very rare non-Hodgkin lymphoma caused by human herpesvirus-8 (HHV8) that grows in liquid phase within body cavities. The diagnosis of PEL is based on cytology but requires confirmatory ancillary tests. PEL occurs mainly in association with HIV infection. This study describes 9 cases of PEL in HIV-negative patients and compares their characteristics with 10 HIV-associated cases of PEL diagnosed at a single institution in Italy between 1995 and 2019. Clinical records were reviewed for demographic data, comorbidities, laboratory abnormalities, and outcome. PEL samples were evaluated for cytomorphology, immunophenotype, immunoglobulin (IG)/T cell receptor (TR) rearrangements, and HHV8 and Epstein-Barr virus (EBV) viral loads in effusion supernatants. HIV-unrelated PEL occurred in 8 elderly patients (7 men, 1 woman) and 1 young adult with primary antibody deficiency. Cytology revealed HHV8-positive lymphoma cells lacking B/T cell antigens and exhibiting 2 cell patterns (polymorphous or monotonous). IG was clonally rearranged in all cases; aberrant TRG occurred in 2 cases. Effusion supernatants had more than 106 HHV8 DNA copies per mL and variable loads of EBV DNA. Compared with HIV-associated PEL, the HIV-negative cohort was characterized by older age, less frequent association with Kaposi sarcoma and/or multicentric Castleman disease, comparable but less abnormal laboratory parameters, and a nonsignificant survival benefit. PEL cases with low apoptosis were associated with better prognosis. To the best of our knowledge, our case series of HIV-unrelated PEL is the largest thus far, expands the spectrum of cytological findings, and supports the need for a multidisciplinary approach in the diagnostic workup.

The Potential Role of Human Herpes Virus-6 in Idiopathic Facial Nerve Paralysis

Background:Bell’s palsy (BP) is an acute, generally unilateral, paralysis or weakness of facial musculature consistent with peripheral facial nerve dysfunction; different factors suspected to contribute to the development of BP including herpesviruses. Objective:To detect human herpes virus 6 (HHV-6) in the saliva samples of patients in the early presentation of BP. Methods: A case-control study included saliva samples taken from 50 patients with BP and 50 apparently healthy controls without any neurological deficit, viral DNA was extracted from the saliva and then subjected for quantitative real time polymerase chain reaction (PCR) for detection of HHV-6 viral load (VL) in saliva. Results: HHV-6 DNA was positive in 22 (44%) out of the 50 patients, and in 12 (24%) of the controls (p=0.028), with a significantly higher mean viral load in patients than control (p=0.002), in addition, 70% of HHV-6 positive patients had severe grades with a significantly higher VL (p=0.007) and (0.015), respectively. Conclusion: HHV-6 could play an important role in the development of BP and HHV-6 might have a neuro-pathological effect in severe cases of BP. Keywords: HHV-6, Bell's palsy, Saliva, real time PCR Citation: Rhaif RH, Al-Obaidi AB, Al-Khazrajee AK. The potential role of Human Herpes Virus-6 in idiopathic facial nerve paralysis. Iraqi JMS. 2020; 18(1): 47-51. doi: 10.22578/IJMS.18.1.7