Human Herpesvirus 6 Infection Research Articles

Mechanism of herpes virus latent infection and its significance

Human herpes virus (HHV) spreads widely in a latent-infected way. HHV is divided into 3 kinds and 8 types. Herpes simplex caused by HHV-1 and HHV-2, varicella-zoster caused by HHV-3 and Epstein-Barr virus (EBV) known as HHV-4 and recognized firstly as human tumor virus, are well known in the field of virology. With the application of hematopoietic stem cell transplantation , cytomegalovirus (HHV-5) and HHV-6 have gained an increasing attention. The biological characteristic of HHV is latent infection in a long time and HHV can be reactivated in some immunocompromised individuals. Clarification of latent infection mechanism will help provide targets for therapy and lay a foundation for clinical treatment. This paper summarizes the clinical significance of HHV infection. Taking the mechanism of EBV latent infection as an example, the pathway and significance as well as strategy of co-evolution of organism and virus will be discussed in order to provide clues for prevention and therapy. Key words: Simplexvirus; Latent infection; Herpesvirus 4, human

Peroxisomes support human herpesvirus 8 latency by stabilizing the viral oncogenic protein vFLIP via the MAVS-TRAF complex.

Human herpesvirus 8 (HHV-8) is causally related to human malignancies. HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its expression is regulated is largely unknown. In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes. Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner. Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases. Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis.

A rare cause of retroperitoneal mass: Castleman's disease

Castleman's disease is a rare lymphoproliferative disorder. It is a pathological diagnosis and rarely diagnosed before surgery. Presentation of disease may be unicentric or multicentric. We are reporting a case of unicentric Castleman's disease presenting as an asymptomatic retroperitoneal mass. The ultrasound-guided aspiration of the lesion was inconclusive. Complete en bloc resection was done and was reported as Castleman's disease after pathological analysis. Pathogenesis of Castleman's disease is not well defined, but interleukin-6 and vascular endothelial growth factor are thought to have a significant role. Two pathological variants have been described as follows: hyaline vascular and plasma cell type. The treatment of unicentric disease is complete resection. Multicentric disease may be associated with human immunodeficiency virus and human herpes virus-8 infection and requires systemic treatment in the form of steroids, chemotherapy, radiotherapy, or immunotherapy.

Prevalence of Human Herpes Viruses in Bronchoalveolar Lavage of Critically Ill Children Undergoing Mechanical Ventilation at a Pediatric Intensive Care Unit

Background: Critically ill children at the intensive care unit frequently develop hospital-acquired pneumonia (HAP). Human herpes viruses (HHVs), primarily or by reactivation may cause bronchopneumonitis in mechanically ventilated patients. The exact prevalence and role of HHVs in morbidity and mortality of pediatric patients undergoing mechanical ventilation is unclear. The current study was conducted to evaluate the prevalence of 5 Herpes viruses by polymerase chain reaction (PCR) method in bronchoalveolar lavage (BAL) samples in critically ill children at a pediatric intensive care unit (PICU). Methods: Overall, 140 bronchoalveolar lavage samples from 83 mechanically ventilated cases were studied. Samples were taken via the mini-BAL technique. Samples were analyzed by qualitative PCR for detection of herpes simplex virus type 1 and 2 (HSV1/HSV2), human herpes virus type 6 and 7 (HHV6/HHV7), Ebstein-Barr virus (EBV), and cytomegalovirus (CMV). Results: Out of 83 cases, 53% (44) were male and 47% (39) were female. The mean age was 29.12 ± 33.67 months (32.53 months in males and 25.29 months in females). The estimated prevalence of HSV1, HHV6, HHV7, EBV, and CMV were 2.4%, 13.2%, 2.4%, 7.2%, and 2.4%, respectively. Conclusions: Molecular study of BAL specimens and investigation of HHVs may be the first step in the evaluation of the possible role of these viruses in the development of viral pneumonia during VAP. The current results are useful for guiding other well-designed studies for correlation of viral load and clinical outcome in ill ventilated children. The Modified protected BAL may be of use as a safe modality in critically ill ventilated pediatric patients for investigation of possible viral (and also bacterial and fungal) infections. Local study of high-risk patients at the PICU and estimation of the true prevalence of HHVs infection may assist in finding the exact role of HHVs in mortality and morbidity of critically ill patients.

Human herpesvirus 6A and 6B and NK cells.

Human herpesvirus 6 (HHV-6) comprises two viral species, HHV-6A and HHV-6B, closely related but differing for pathogenic and biological characteristics. Both viral species are predominantly lymphotropic, infecting T lymphocytes and other lymphoid cells, including natural killer (NK) cells. The interactions between HHV-6 and NK cells have been scarcely studied, but it has become clear that NK cells are not only crucial in immune protection during the early phases of infection, but also that HHV-6 infection can affect NK cell functions. In this report, we shortly summarize the interactions between HHV-6 and NK cells.

Scrotal Kaposi's Sarcoma in HIV-negative patient: A case report and review of the literature.

Kaposi's Sarcoma (KS) is a malignancy that generally effects the skin, and can be systemic with internal organ involvement. It originates from the vascular endothelium. KS's relationship with human immunodeficiency virus (HIV) infection is well known. Isolated scrotal KS in the urogenital system is quite rare and scrotal KS in an HIV-negative patient is limited to a few cases. In this case report, the biopsy result from the violescent nodular lesions on the scrotum of the HIV-negative 81-year-old patient was found compatible with KS and a pathology was not detected in the systemic screening. With a diagnosis of isolated scrotal KS, the patient underwent surgical excision aimed at the lesions on the scrotum. KS is rare in HIV-negative patients and it is associated with human herpes virus-8 infection.

Exogenous human herpesvirus 6 reinfection after tumor-infiltrating T-lymphocyte therapy

Exogenous human herpes virus 6 (HHV-6) reinfection has never been reported in patients receiving tumor-infiltrating T lymphocytes therapy. We report an unusual case of HHV-6 infection following infusion of HHV-6 infected autologous T lymphocytes. HHV-6 infection could interfere with the tumor antigen immune recognition and the efficacy of immunotherapy.

The Activation of Cytomegalovirus and Human Herpes Virus 6 After Liver Transplantation

Background: Cytomegalovirus (CMV) and Human Herpes Virus-6 (HHV-6) activation after liver transplantation have been associated with increased graft rejection and adverse outcomes. This study aimed at investigating the development and timing of CMV infection after liver transplantation and its relation to post-transplantation HHV-6 activation. Methods: Patients undergoing liver transplantation were enrolled, regardless of their age, place of residence, or their liver failure etiology. Blood samples were collected at baseline and every week for a period of 12 weeks and were tested for anti-CMV IgG and anti-HHV-6 IgG, CMV pp65 antigenemia, as well as CMV and HHV-6 DNA using the Polymerase Chain Reaction (PCR) method. Results: Among 46 liver transplant recipients, 17 (36.9%) developed CMV infection within 3 months after transplantation. Before transplantation, 42 (91.3%) and 41 (89.1%) recipients were seropositive for CMV and HHV-6, respectively. Fifty percent of patients were positive for CMV antigenemia, among which 73.9% became symptomatic for CMV infection. Half of the patients had positive test results for CMV PCR with a significant relationship between the CMV viral load and the development of symptomatic CMV infection (P = 0.001). Twenty-five (54.3%) patients had positive test results for HHV-6 PCR with a significant relationship between HHV-6 positivity and the development of clinical presentation (P = 0.002). The average post-transplantation time to HHV-6 and CMV activation was 19.4 ± 86.5 and 28.4 ± 60.5 days, respectively, with a linear relationship in the regression analysis. Conclusions: The HHV-6 infection, either as primary infection or reactivation, leads to an increased risk of CMV infection and symptomatic disease after liver transplantation. Activation of HHV-6 precedes the CMV activation in time.

Kaposi sarcoma incidence in females is nearly four-fold higher in the Lower Rio Grande Valley compared to the Texas average

The Lower Rio Grande Valley (LRGV) is located on U.S.-Mexican border with a population that is 90% Hispanic [1]. Comprised of Hidalgo, Cameron, Starr and Willacy counties, this region has the highest poverty rate and one of the highest incidences of Type 2 diabetes in the United States [2–4]. Previous studies demonstrated a high prevalence of Human Herpes Virus 8 (HHV8) in the LRGV [5–7]. HHV8 infection has been causally linked to Kaposi Sarcoma (KS) [8]. Here, we retrospectively examine the incidence of KS in the LRGV in a set of HIV-negative Hispanic patients. Strikingly, the incidence of KS was higher in LRGV women compared to the Texas state average (nearly four-fold higher in McAllen-Edinburg-Pharr Metro Statistical Area). This unique profile aligns with the increased HHV8 prevalence in the LRGV, suggesting that HHV8 contributes to a high incidence of HIV-negative KS on the U.S.–Mexican border in Texas.

Viruses in chronic progressive neurologic disease

Viruses have long been implicated as triggers of disease onset and progression in multiple sclerosis (MS) and similar neuroinflammatory disorders. Decades of epidemiological, molecular, and pathologic studies have most strongly linked the human herpesviruses Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) with MS. However, these viruses are ubiquitous in the general population and typically acquired decades before disease presentation, complicating the study of how they might contribute to disease. As experimental animal models may help elucidate mechanisms that have linked viruses with MS, we have been studying HHV-6 infections in a small nonhuman primate. We recently demonstrated that the subsequent induction of an MS-like experimental neuroinflammatory disease results in significantly accelerated disease in HHV-6 inoculated marmosets compared to controls. Ultimately, disease intervention in the form of clinical trials with an antiviral agent is the best way to concretely demonstrate a role for HHV-6 or any other virus in MS.

No indication of increased infection rates using low-dose alemtuzumab instead of anti-thymocyte globulin as graft-versus-host disease prophylaxis before allogeneic stem cell transplantation.

Alemtuzumab as part of the conditioning protocol is effective in reducing graft-versus-host disease (GvHD), but may be associated with increased infection rates, especially when using high doses (ie, 100mg). We performed a retrospective, single-center, case-control study analyzing the rates of neutropenic fever, cytomegalovirus (CMV) reactivation, Epstein-Barr virus (EBV) reactivation, clinical manifest toxoplasmosis, and clinical manifest human herpesvirus-6 (HHV6) infection using low-dose alemtuzumab in comparison with anti-thymocyte globulin (ATG) as GvHD prophylaxis before allogeneic stem cell transplantation. Forty-four patients transplanted from unrelated donors between 2001 and 2012 were matched by age, diagnosis, and conditioning regimen and treated either with alemtuzumab 10mg at day -2 (respectively, 20mg in case of mismatch transplantation) or ATG. ATG Fresenius (10mg/kg for 3days) or Thymoglobulin (2mg/kg for 3days) were used. Rates of CMV reactivation, EBV reactivation, and clinical manifest HHV6 infection or toxoplasmosis did not differ significantly between both groups until 2years after transplantation. No case of post-transplant lymphoproliferative disorder was observed. Also, rates of neutropenic fever during inpatient treatment after transplantation did not differ significantly in both groups. We saw no indication of increased infections rates when using low-dose alemtuzumab as GvHD prophylaxis before allogeneic stem cell transplantation in this retrospective analysis.

Epigallocatechin-3-Gallate Suppresses Human Herpesvirus 8 Replication and Induces ROS Leading to Apoptosis and Autophagy in Primary Effusion Lymphoma Cells.

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to induce cell death in cancer cells. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by human herpesvirus 8 (HHV8). In this study, we examined the role of EGCG on PEL cells in cell death and HHV8 replication. We performed trypan blue exclusion assay to assess the cell viability of PEL cells, flow cytometry analysis to examine the cell cycle distribution and reactive oxygen species (ROS) generation, caspase-3 activity to assay apoptosis, acridine orange staining to determine autophagy, and immunoblotting to detect the protein levels involved in apoptosis and autophagy as well as mitogen activated protein kinases (MAPKs) activation upon EGCG treatment. The expression of the HHV8 lytic gene was determined by luciferase reporter assay and reverse transcription-PCR, and viral progeny production was determined by PCR. Results revealed that EGCG induced cell death and ROS generation in PEL cells in a dose-dependent manner. N-acetylcysteine (NAC) inhibited the EGCG-induced ROS and rescued the cell from EGCG-induced cell death. Even though EGCG induced ROS generation in PEL cells, it reduced the production of progeny virus from PEL cells without causing HHV8 reactivation. These results suggest that EGCG may represent a novel strategy for the treatment of HHV8 infection and HHV8-associated lymphomas.

Human Herpesvirus 8 Infects and Replicates in Langerhans Cells and Interstitial Dermal Dendritic Cells and Impairs Their Function.

ABSTRACTThe predominant types of dendritic cells (DC) in the skin and mucosa are Langerhans cells (LC) and interstitial dermal DC (iDDC). LC and iDDC process cutaneous antigens and migrate out of the skin and mucosa to the draining lymph nodes to present antigens to T and B cells. Because of the strategic location of LC and iDDC and the ability of these cells to capture and process pathogens, we hypothesized that they could be infected with human herpesvirus 8 (HHV-8) (Kaposi's sarcoma [KS]-associated herpesvirus) and have an important role in the development of KS. We have previously shown that HHV-8 enters monocyte-derived dendritic cells (MDDC) through DC-SIGN, resulting in nonproductive infection. Here we show that LC and iDDC generated from pluripotent cord blood CD34+ cell precursors support productive infection with HHV-8. Anti-DC-SIGN monoclonal antibody (MAb) inhibited HHV-8 infection of iDDC, as shown by low expression levels of viral proteins and DNA. In contrast, blocking of both langerin and the receptor protein tyrosine kinase ephrin A2 was required to inhibit HHV-8 infection of LC. Infection with HHV-8 did not alter the cell surface expression of langerin on LC but downregulated the expression of DC-SIGN on iDDC, as we previously reported for MDDC. HHV-8-infected LC and iDDC had a reduced ability to stimulate allogeneic CD4+ T cells in the mixed-lymphocyte reaction. These results indicate that HHV-8 can target both LC and iDDC for productive infection via different receptors and alter their function, supporting their potential role in HHV-8 pathogenesis and KS.IMPORTANCE Here we show that HHV-8, a DNA tumor virus that causes Kaposi's sarcoma, infects three types of dendritic cells: monocyte-derived dendritic cells, Langerhans cells, and interstitial dermal dendritic cells. We show that different receptors are used by this virus to infect these cells. DC-SIGN is a major receptor for infection of both monocyte-derived dendritic cells and interstitial dermal dendritic cells, yet the virus fully replicates only in the latter. HHV-8 uses langerin and the ephrin A2 receptor to infect Langerhans cells, which support full HHV-8 lytic replication. This infection of Langerhans cells and interstitial dermal dendritic cells results in an impaired ability to stimulate CD4+ helper T cell responses. Taken together, our data show that HHV-8 utilizes alternate receptors to differentially infect and replicate in these tissue-resident DC and support the hypothesis that these cells play an important role in HHV-8 infection and pathogenesis.

Seroprevalence of Human Herpesvirus Type 2 in a Reference Center for Pregnant Women in Rio de Janeiro, Brazil

Introduction: Pregnant women stand as an relevant group for research about Human Herpesvirus (HHV-2) infection owing to the risk of mother-to-child transmission. Methods: Women attending in a prenatal care center were tested for HHV-2 IgM and IgG by ELISA. Quantitative PCR test was the chosen method to ascertain viremia. Results: The seroprevalence of IgG and IgM anti-HHV-2 was 20.6% and 2.2% respectively. HHV-2 viremia was found in one pregnant woman with HHV-2 IgM, leading to the assumption of primary infection. Conclusion: The significantly high prevalence of HHV-2 found and the ascertainment of primary infection in a pregnant woman underline the need for constant HHV-2 follow-up and diagnosis in order to avoid sexual transmission.

EBV and HHV-6 Circulating Subtypes in People Living with HIV in Burkina Faso, Impact on CD4 T cell count and HIV Viral Load.

Epstein Barr Virus (EBV) and Human Herpes Virus 6 (HHV-6) are responsible for severe diseases, particularly in immunocompromised persons. There is limited data of the infection of these opportunistic viruses in Burkina Faso.The purpose of this study was to characterize EBV and HHV-6 subtypes and to assess their impact on CD4 T cell count, HIV-1 viral load and antiretroviral treatment in people living with HIV-1. The study population consisted of 238 HIV-positive patients with information on the CD4 T cell count, HIV-1 viral load and HAART. Venous blood samples collected in EDTA tubes were used for EBV and HHV-6 Real Time PCR subtyping.An infection rate of 6.7% (16/238) and 7.1% (17/238) were found respectively for EBV and HHV-6 in the present study. Among EBV infections, similar prevalence was noted for both subtypes (3.9% (9/238) for EBV-1 vs 4.6% (11/238) for EBV-2) with 2.1% (5/238) of co-infection. HHV-6A infection represented 6.3% (15/238) of the study population against 5.0% (12/238) for HHV-6B. EBV-2 infection was significantly higher in patients with CD4 T cell count ≥ 500 compared to those with CD4 T cell count less than 500 cells (1.65% vs 8.56%, p = 0,011). The prevalence of EBV and HHV-6 infections was almost similar in HAART-naive and HAART-experienced patients.The present study provides information on the prevalence of EBV and HHV-6 subtypes in people living with HIV-1 in Burkina Faso. The study also suggests that HAART treatment has no effect on infection with these opportunistic viruses in people living with HIV-1.

Association of Household Food- and Drink-Sharing Practices With Human Herpesvirus 8 Seroconversion in a Cohort of Zambian Children.

Human herpesvirus 8 (HHV-8) infection occurs in early childhood and is associated with human immunodeficiency virus type 1 (HIV-1) infection and risk for Kaposi sarcoma, but behaviors associated with HHV-8 transmission are not well described. We enrolled and followed a prospective cohort of 270 children and their household members to investigate risk factors for HHV-8 transmission in Lusaka, Zambia. We report an incidence of 30.07 seroconversions per 100 child-years. Independent risk factors for HHV-8 incident infection included having a child who shared utensils with a primary caregiver (hazards ratio [HR], 2.33; 95% confidence interval [CI], 1.49-7.14), having an increasing number of HHV-8-infected household members (HR, 1.27; 95% CI, 1.09-2.79), and having ≥5 siblings/children in the household (HR, 2.24; 95% CI, 1.03-4.88). Playing with >5 children a day was protective against infection (HR, 0.54; 95% CI, .33-0.89), as was increasing child age (HR, 0.96; 95% CI, .93-.99). This is the first study to find a temporal association between limited child feeding behaviors and risk for HHV-8 infection. Child food- and drink-sharing behaviors should be included in efforts to minimize HHV-8 transmission, and households with a large number of siblings should receive additional counseling as childhood infections occur in the home context.

Multicenter Prospective Study for Laboratory Diagnosis of HHV8 Infection in Solid Organ Donors and Transplant Recipients and Evaluation of the Clinical Impact After Transplantation.

We performed serological and molecular pretransplant screening in solid organ transplant (SOT) donors and recipients in north central Italy and a surveillance program for human herpesvirus 8 (HHV8) infection after transplant, aiming to establish an optimal management of HHV8 infection in SOT recipients. For pretransplant HHV8 screening in both donors and recipients, 6 serological (4 indirect immunofluorescent assays [IFA] and 2 enzyme-linked immunosorbent assays-both HHV8 lytic and latent antigen based) and 2 molecular assays were used. A reference standard to identify HHV8-positive patients was defined by at least 2 positive assays. All transplant patients at risk to develop HHV8-related disease underwent virological posttransplant monitoring by quantitative real-time polymerase chain reaction (PCR) assay. Human herpesvirus 8 seroprevalence was 4% (10/249) in donors and 18% (93/517) in organ recipients. The best performance was obtained by 2 lytic antigen-based IFAs that showed almost perfect agreement to the reference standard (0.943 and 0.931 Cohen kappa). Human herpesvirus 8-DNA was detected in 6.8% and 2.9% of HHV8-seropositive donor samples by in-house nested PCR and quantitative real-time PCR assays, respectively. After transplant, 3 (25%) of 12 HHV8-mismatch patients (seropositive donor/seronegative recipient) developed a primary infection, one of whom developed a lethal nonmalignant illness. Two of 93 HHV8-seropositive recipients (2.1%) had viral replication in posttransplant period, one of whom developed Kaposi sarcoma. Serological assays, specifically lytic IFAs, were the best methodological approach to identify HHV8-infected SOT donors and recipients. A very low incidence (1.9%) of posttransplant HHV8-related disease was observed.

Significance of PCR detection of HHV6 in gastro biopsy on the course of diarrhea in patients with severe diarrhea after allogeneic hematopoietic stem cell transplantation

目的探讨肠黏膜人疱疹病毒6型（HHV6）检测在异基因造血干细胞移植（allo-HSCT）术后重度腹泻患者中的意义。方法回顾性分析2015年2月至2016年8月于北京大学血液病研究所行allo-HSCT后出现重度腹泻并行肠镜检查及肠黏膜活检的患者资料；HHV6、CMV、EBV检测采用RT-PCR方法；肠黏膜病理检查也包括免疫组化方法检测CMV早期抗原、CMV晚期抗原，原位杂交检测EBV。结果共有45例患者纳入研究，其中21例（46.7%）肠黏膜活检HHV6阳性，包括男13例，女8例，中位年龄29（14~54）岁；肠黏膜HHV6阳性与阴性组患者血CMV阳性检出率差异无统计学意义（76.2%对87.5%，P>0.05），但EBV血症发生率前者（6/21，28.6%）明显高于后者（1/24，4.2%）（P=0.028）；两组患者在腹泻发生的时间、次数及量方面差异无统计学意义（P值均>0.05）。45例患者中44例接受了膦甲酸钠和（或）更昔洛韦抗病毒治疗，抗病毒治疗并没有影响腹泻的进程。结论肠黏膜HHV6阳性在allo-HSCT术后重症腹泻患者中发生率高，未发现其对于治疗及预后有临床意义。肠黏膜HHV6阳性并不能证明HHV6在肠道的感染。

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.

Association between human herpesvirus infections and dementia or mild cognitive impairment: a systematic review protocol

IntroductionPersisting neurotropic viruses are proposed to increase the risk of dementia, but evidence of association from robust, adequately powered population studies is lacking. This is essential to inform clinical trials...