The association of HHV6 with MS

MS is the most prevalent demyelinating disease of the CNS (Pugliatti et al., 2002). The variability of the diseases suggests that many factors, including genetic and immune components, are involved in the spectrum of clinical syndromes that are defined as MS. In addition, epidemiological, laboratory, and clinical findings suggest that an infectious agent(s) (Marie, 1895 Johnson, 1994) may be involved in the induction and progression of this disorder (reviewed in Soldan and Jacobson, 2001). Over...

The epidemiology of roseola from historical observations

The epidemiologic picture of human herpesvirus 6 (HHV6) has continually evolved over its known life span of 2 decades. Still, it remains more of a collage than a completed portrait, for HHV6 has multiple characters. It is a covert companion of life, and yet a mimicker of many maladies. Although HHV6 was named relatively recently, this virus probably has long been recognized as an exanthematous disease of childhood. In papers and texts from the 1800s, an acute infection of young children with...

Summary

CFS patients often show evidence of immune dysfunction and or dysregulation, such as low suppressor cell numbers, low numbers and efficacy of NK cells, and abnormal RNase L. These dysfunctions are manifest when the immune system is challenged by a virus or other infection, suggesting that there might be a viral trigger that initiates and or perpetuates CFS. Active infection by HHV-6 is found in association with patients suffering from CFS in significantly greater proportion than in the healthy...

Future assay methods

New approaches to the detection and quantitation of HHV-6 DNA in clinical specimens include non-PCR-based gene amplification or detection methods such as branched DNA (bDNA) hybridization (Urdea et al., 1987) and isothermal amplification (Guatelli et al., 1990 Walker et al., 1992 Ihira et al., 2004). Fig. 1 Alignment of HHV-6A and HHV-6B. A Inter-variant alignment (HHV-6A U1102 and HHV-6B Z29). B Intra-variant alignment (HHV-6B HST and HHV-6B Z29). Shown is a visual overview of the overall...

Conclusions

The CVS may be the target of HHV-6 infection with the primary target being endothelial cells, which express the CD46 complement receptor on their cell membranes. Isolated cases of vascular disease and myocarditis related to HHV-6 infection have been reported. More recent evidence has indicated a high rate of recovery of HHV-6 viral genome in myocardium of patients with cardiomyopathy and unexplained left ventricular dysfunction. A consistent pattern of coinfection with HHV-6 and parvovirus B19...

HHV6 association with other liver disease

As shown in the Table 1, HHV-6 is associated with a variety of diseases causing liver damage. Because of the different pathophysiology of these conditions, the role and mechanism of HHV-6 in hepatic damage in these diseases is unclear. HHV-6 may be associated with Gianotii-Crosti syndrome, a popular acroder-matitis of childhood causing mild elevations of hepatic transaminase, and hepatitis B virus plays an important role in the pathogenesis of this disease. A case report described an...

Biological aspects of variants A and B

HHV-6 is predominantly a T-lymphotropic virus, but it has the ability to infect other cell types (Ablashi et al., 1988 Braun et al., 1997). Both HHV-6A and B replicate efficiently in activated peripheral blood or cord blood mononuclear cells. HHV-6, especially HHV-6A, is more cell associated. Isolating HHV-6B from peripheral blood from patients with Exanthem subitum or from transplant patients is much easier than isolating HHV-6A. Although HHV-6A DNA copy numbers in peripheral blood mononuclear...

Factors affecting acquisition of HHV6 infection

Geographical location may affect the frequency and age of occurrence of HHV6 infection, as noted above. However, some of the variation in seroprevalence among countries may be the result of differing methods for the laboratory assays utilized and for the selection of the populations surveyed. Seroprevalence studies in general have not shown that the rate of antibody positivity is appreciably affected by ethnic background, socioeconomic factors, or gender. A few reports have shown a slightly...

Abstract

The emergence of human immunodeficiency virus (HIV) in the 1980s heightened our awareness that immunodeficiency could be acquired through viral infection. Historically, measles and hepatitis B and C viruses were implicated as immuno-suppressive viruses however, there is growing evidence that a number of the her-pesviruses have properties similar to HIV with serious clinical sequelae. This chapter is devoted to a discussion of the impact of human herpesvirus-6 (HHV-6) infection on the immune...

Case report

A 47-year-old man was referred to our hospital on December 29, 1997 because of an exacerbation of fulminant myocarditis after undergoing steroid pulse therapy with methylprednisolone and plasma apheresis for acute hepatitis and acute myocarditis at another hospital. About two weeks earlier, he presented with a low-grade fever, general fatigue, cough, anorexia, and nausea. On December 20, 1997, he was admitted to a hospital because the symptoms worsened. A physical examination revealed a heart...

Clinical spectrum and systemic manifestations

Usually, high and spiking fever begins this syndrome (Knowles et al., 1999 Begon and Roujeau, 2004). Fever precedes or is concomitant to the onset of the cutaneous manifestations. Fever and skin eruption are the most common clinical manifestations. Skin manifestations are usually a maculopapular exanthema with facial edema (periorbital), which may progress to an exfoliative dermatitis (erythroderma) (Fig. 1). Sometimes pustulosis, blistering, or oral ulceration may occur. Rarely, more serious...

Eae

Marmoset model 309-10 ears, HHV-6 primary infection in children 174-6 EBV see Epstein-Barr virus enanthema, with Nagayama's papules 177f encephalitis 84, 98, 282t endothelial cells 64, 65, 142, 226, 234, 235f endothelial dysfunction 238-9 enterovirus 225 envelope 12, 15 envelope glycoproteins 52 envelope-mediated cell fusion assay 60 enzyme immunoassays 93-4 enzyme-linked immunosorbent assay (ELISA) 92, 93-4, 94, 95, 187 epidemiology 81, 119 animal model 307-8 incubation period 125-6 mode of...

Pathogenesis of HHV6associated hepatitis

As described above, HHV-6 can directly cause hepatitis, but its mechanism of liver injury is unknown. HHV-6 may directly damage hepatocytes, or the immune and inflammatory response to the virus may cause liver damage. HHV-6 DNA, RNA, and antigens were detected in the hepatocytes of affected livers by in situ hybridization analysis (Mason et al., 1996 Ozaki et al., 2001 Ishikawa et al., 2002). These observations strongly suggest HHV-6 has the potential to directly damage he-patocytes during...

HHV6 exhibits transforming capacities

The 3.9 kbp Sall-L fragment located within the direct repeat region of HHV-6 variant A was shown to transform the murine NIH3T3 cell line, human epidermal keratinocytes RHEK-1, and both primary and established rodent cells (Razzaque et al., 1993 Thompson et al., 1994). This transforming activity was localized to the DR7 gene and cells expressing DR7 protein-induced tumours when injected into immunodeficient nude mice, while cells expressing truncated DR7 protein did not (Kashanchi et al.,1997)....

Cellular and tissue host range in vivo

Only a few studies have carefully investigated the tissue host range of HHV-6 in vivo. During acute primary infection, HHV-6B has been identified primarily in CD4+ T-cells (Takahashi et al., 1989), which not only represent the primary target for virus replication, but may also function as a reservoir for HHV-6 latency. However, high levels of HHV-6 DNA have also been detected in circulating mon-ocytes during primary infection, and virus isolation was successfully achieved from these cells...

Subversion of the immune system

It is unclear whether preexisting immunodeficiency is necessary for infection with HHV-6 or whether this virus uses stealth strategies for initial entry and then exerts its immunosuppressive effects. However, it is clear that once infection has occurred, HHV-6 is able to establish latency and remain quiescent for prolonged periods of time unless the immune system is otherwise immunocompromised. One of the mechanisms by which viruses establish long-lived infections and subvert the immune system...

Solid organ transplant recipients

Overall, 38-55 of renal, 22-54 of liver, 36 of heart and up to 57 of heart-lung lung transplant recipients have been shown to develop HHV-6 infection (Morris et al., 1989 Okuno et al., 1990 Herbein et al., 1996 Dockrell et al., 1997 Lautenschlager et al., 2000 Rogers et al., 2000 de Ona et al., 2002). Following living related liver transplantation, HHV-6 infection has been documented in 48 of the patients these included 4 4 patients who were seronegative and 42 (15 36) of those who were...

HHV6 infection can induce atypical lymphoproliferations

Atypical lymphoproliferations (APLs) constitute a heterogenous group of lesions that clinically mimic malignant lymphomas, but are lacking the criteria of mon-oclonality and malignant transformation. The incidence of APL seems to be increased in patients with immune disorders, and persistently active infection by lymphotropic viruses is frequently found in APLs. They can be defined as prema-lignant lymphoproliferations and may finally transform to malignant lymphomas. Type B reticulum cell...

HHV6 reactivation in DRESS innocent bystander or causal agent of systemic symptoms

HHV-6 is perhaps the best example of an opportunistic viral infection that may reactivate in stress condition or immunosuppression. HHV-6 may reactivate in the case of immune dysregulation or deficiency. Selective reactivation of HHV-6 was demonstrated in critically ill immunocompetent patients (Desachy et al., 2001 Razonable et al., 2002). It is becoming recognized as an emerging pathogen among transplant recipients. We and others wondered whether (1) HHV-6 played a causal role in DRESS and...

A5021 297

AAV-2 rep homologue 51-2 acute and chronic infections 330-2 serologic testing 91-100 acute lymphoblastic leukaemia 195 acute primary infection 65, 143 acyclovir 258, 286-7, 293, 296 adenovirus 238, 248 AIDS 271, 272-4 HHV-6, opportunistic agent 269, 270 related LD 194-5 alpha interferon 338 alphaherpesvirus 12, 13 amplicons 28 ampligen 259 angioimmunoblastic lymphadenopathy disease (AILD) 193-4 animal models 305-16 anti-herpesvirus therapy, new targets 297-9 anti-inflammatory (Th2) cytokine...

Exanthem subitum

Primary infection with HHV-6B causes exanthem subitum, a common febrile disease in infants (Yamanishi et al., 1988). In Japan, more than 90 of infants with primary HHV-6 infection visiting our clinic with high fever exhibited a typical clinical course of exanthem subitum (Asano et al., 1994). Additionally, about 80 of young children from several day nurseries with positive anti-HHV-6 antibody titers had a past history of exanthem subitum (unpublished data). Thus, we estimated that 70-80 of...

Pityriasis rosea and HHV6

Pityriasis rosea is a common, acute, self-limiting papulosquamous skin disorder. The initial skin lesion is called the herald patch,'' and typically appears on the trunk as a 2-3 cm oval scaly plaque with a central salmon-colored area and a darker erythematous peripheral zone. The disease normally resolves spontaneously within 4-8 weeks. The clinical and epidemiological features of this disease suggest a pathogenic role for an infectious agent. Drago et al. (1997) first suggested that...

Immune modulation

The broad immunotropism of HHV-6, particularly of variant A (Table 1), may dramatically affect, directly or indirectly, the function of the cellular and humoral arms of the immune system. As discussed above, both variants have a primary tropism for CD4+ T cells, which are pivotal in the orchestration of the immune responses. Variant A also efficiently infects different types of cytotoxic effector cells such as CD8+ T lymphocytes, NK cells, and gd T lymphocytes. Moreover, both mononuclear...

Bone marrow transplant

The immunosuppressive regimens used in bone marrow transplant (BMT) tend to be even more severe than those in solid organ transplant. Most BMT recipients are immunocompromised initially by their underlying disease that is further exacerbated by total body irradiation, lymphodepleting antibodies, steroids, and the anti-pro-liferative drugs associated with chemotherapy. Although the immunosuppressive protocol for allogeneic transplants is considerably more aggressive than autologous transplants,...

Characterization of HHV6specific antibodies

The determination of antibody isotype is an important issue in the general strategies of viral diagnosis. In most acute viral infections, IgM is the predominant antibody produced at the early phase of primary immune response, and its detection in a single serum specimen is sufficient to suggest that the infection is recent. However, in the case of herpesviruses, IgM may also be detected during viral reactivation from latency. The heterotypic reactivation of IgM, for instance during human...

Discussion and conclusions

Twenty years after its discovery, HHV-6 is an emerging pathogen with an increasing body of data to support disease associations spanning the self-limiting rash of childhood to the ravages of multiple sclerosis. Applying scientific rigor to assessing these associations will be necessary to verify the etiology of these diseases particularly those like fibromyalgia, which remains very difficult to diagnose. The development of additional immunological research tools (both cellular and humoral) as...

Disease associations of HHV6A and 6B variants

It was previously thought that primary infection of HHV-6 in infants and young children lead to roseola and febrile illnesses. This infection was attributed to HHV-6B (Yamanishi et al., 1988). Some of the symptoms identified include diarrhea, vomiting, seizure, nasal congestion, rash and high fever. Similar symptoms were noted in Africa in children and the DNA analysis from the peripheral blood from these children revealed HHV-6A infections (Hidaka et al., 1997 Kasolo et al., 1997 Randhawa et...

Diseases of blood vessels

Replicative and latent infection of vascular endothelium by HHV-6 was repeatedly shown in vivo and in vitro using immunohistochemical and molecular techniques (Wu and Shanley, 1998 Rotola et al., 2000 Caruso et al., 2003). In vitro infection of human umbilical vein endothelium (HUVEC) with HHV-6 was followed by the expression of early and late viral antigens in 37.6 and 6.5 of HUVEC, respectively, with persistence of the antigens for up to 27 days. Although virus was not obviously released from...

HHV6 association with CFS

One of the first reports of isolated post-infectious fatigue associated with encephalitis, lymph proliferation, and the presence of HHV-6 infection, was made by Buchwald et al. (1990). Daugherty et al. (1991) also reported a group of patients with profound fatigue lymphadenopathy and cognitive dysfunction associated with evidence of HHV-6 reactivation, although variant analysis was not available at that time. Early studies of CFS patients demonstrated an increase in serum IgG and IgM for HHV-6...

General cellular pathology of HHV6 infection

In vitro studies show the immediate effects of HHV-6 binding to cells, infection of susceptible cells and intracellular replication (see also Chapter 2 Ultrastructure of HHV-6). Susceptible cells (e.g. HSB2, cord blood cells) show upon exposure to HHV-6 blastic transformation with or without giant cell formation, intranuclear inclusions, eventual mitoses and production of viral particles with cellular degeneration and apoptosis (Fig. 1 Biberfeld et al., 1987 Kramarsky and Sander, 1992 Kirn et...

HHV6 is found essentially in scleronodular HD in young adults

EBV, another herpesvirus frequently associated with HD, is not distributed equally among the different subtypes of EBV-positive HD 70 of mixed cellularity, > 95 of lymphocyte depleted, 10-40 of nodular sclerosis, and almost absent from lymphocyte-predominant HD subtypes. In addition, HD cases associated with EBV occurred most frequently in children or in elderly people. Previous epidemiological studies suggested multiple etiologies for HD and led to the hypothesis of an infectious viral...

HHV6 therapy in CFS patients

CFS patients with active infection by HHV-6 (variants A or B) can be treated with antivirals or immune modulatory agents in order to relieve the symptoms of fatigue and minimize CNS complaints. Acyclovir has remained the gold standard of treatment for herpes viral infections in general. However, pilot studies using acyclovir and ganciclovir showed persistence of HHV-6 variant A in spinal fluid even after treatment (Peterson, unpublished studies). HHV-6 does not encode thymidine kinase, and thus...

Human Herpesvirus6 Infection in Solid Organ and Stem Cell Transplant Recipients

AKarolinska University Hospital, Karolinska Institutet, Stockholm, Sweden b University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA Seroepidemiologic studies have shown that infection due to human herpesvirus-6 (HHV-6) is usually acquired during the first year of life the virus subsequently persists in the host. Seroprevalence in healthy adults exceeds 90 . Serology is unable to differentiate between the two subtypes and therefore it is possible that seropositive patients might...

Kshv

Plate 4 Sub-families of Human Herpesviruses. (see page 8). Plate 5 CryoEM imaging and 3D reconstruction HSV-6 capsid. (a) A gallery of cryoEM particle images of HHV-6 capsids. (b) Shaded surface representation of HHV-6 capsid reconstruction at 30 A resolution. The structure is color coded according to capsid radius so that the capsid shell is in yellow, the triplexes are in green, and the upper domains of the pentons and hexons are in purple. (see page 17). Plate 6 Comparison of HSV-1, HCMV,...

Lieve Naesens Leen De Bolle Erik De Clercq

Faculty of Pharmaceutical Sciences, Ghent University, B-9000 Gent, Belgium In contrast to other human herpesviruses such as herpes simplex virus (HSV) or cytomegalovirus (CMV), HHV-6 has not been the subject of extensive antiviral screening, the main reason being the uncertainty about the large need for specific anti-HHV-6 therapies. Transplant recipients commonly show laboratory signs of HHV-6 reactivation, but the frequency by which this is associated with serious disease is still ill defined...

Lymphatic and hematopoietic system see also chapters 14 and

In chronic persistent HHV-6 infection, viral DNA load and cellular changes show certain cyclic changes, suggesting some fluctuation in viral replication (Krueger et al., 2001). In about 6 , heterophile-negative infectious mononucleosis is caused by HHV-6A or B infection (Steeper et al., 1990 Horwitz et al., 1992 Akashi et al., 1993). More frequent is the reactivation of latent HHV-6 in patients with classical EBV-induced infectious mononucleosis resulting in a more protracted course of the...

Skin rash and HHV6 reactivation in hematopoietic stem cell transplant recipient

Several clinical conditions such as skin rash resembling acute GVHD, bone marrow suppression, interstitial pneumonitis, and encephalitis, may be related to HHV-6 infection after HSCT (Yoshikawa, 2004b). Moreover, an association between HHV-6 infection and acute GVHD was suggested in HSCT recipients. HHV-6 and human Studies for evaluation of clinical features in primary HHV-6 infection (exanthem subitum) Studies for evaluation of clinical features in primary HHV-6 infection (exanthem subitum)...

HHV6 and PML

PML is an often fatal disorder of the CNS that primarily affects individuals with impaired immune systems including patients treated for cancers such as leukemia or lymphoma, allograft recipients, and up to 10 of patients with AIDS (Padgett et al., 1971 Berger and Major, 1999). The etiologic agent of PML is JC virus (JCV), a human neurotropic member of the polyomaviruses a family of non-enveloped tumor viruses with small, circular, double-stranded DNA genomes. JCV is widespread throughout the...

Discovery and Classification of Human Herpesvirus6 HHV6

AHHV-6 Foundation, 285 San Ysidro Road, Santa Barbara, CA 93108, USA bDepartment of Microbiology & Immunology, Georgetown University School of Medicine, Washington, DC, USA The discovery of herpesvirus-6 (HHV-6) dates back to early 1985 when Zaki Sal-ahuddin, in Dr. Robert Gallo's Laboratory of Tumor Cell Biology, was establishing long-term cultures from peripheral blood and splenic tissue of AIDS patients. He frequently found large syncytia that were distinct from HIV-1-induced syncytia....

HHV6 Genome Similar and Different

ADepartment of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, University of London, UK b Virology Unit, University Teaching Hospital, Lusaka, Zambia cAFRO VPD, World Health Organisation, Harare, Zimbabwe Roseoloviruses, human herpesviruses 6 and 7 (HHV-6, HHV-7) are widespread T lymphotropic and neurotropic viruses causing mostly benign infections. However, particularly for HHV-6, during some primary as well as secondary reactivated infections, which can...

HHV6 and hepatitis

Primary HHV-6 B infection causes exanthem subitum, a common febrile infant disease (Yamanishi et al., 1988). Although only 17 of American children with primary HHV-6 infection develop exanthem subitum (Pruksananonda et al., 1992), in Japan, 70-80 of infants with primary viral infection exhibit a typical clinical course of exanthem subitum (Asano et al., 1991a). Most affected patients visit a pediatric outpatient clinic, and some receive hematological examination to rule out severe infectious...

Nonprimary HHV6 infection and the respiratory tract

As more than 95 of HHV-6 infections occur during the first two years of life, most HHV-6 infections observed at later ages (especially in teens and adults) are probably reactivations of latent infections or de novo infections with a second virus (Krueger et al., 1998b Ablashi and Krueger, 2003). Non-primary HHV-6 infections of the respiratory tract occur preferentially in immunodeficient patients, yet may occasionally also be seen in not obviously compromised persons. Any conclusion about HHV-6...

Pathophysiology of HHV6 reactivation in DRESS

The mechanism by which HHV-6 is reactivated and participated in the development of DRESS is not yet understood. Many factors are probably implicated in DRESS as recently summarized by Wong and Shear (2004) drug exposure, genetic predisposition, drug interactions, concomitant illness, host immune response with generation of drug-specific T cells, cytokines, transient hypogammaglobulinemia, reactivation of latent viral infection, viral infection, etc. A genetic predisposition is obviously...

Joseph H Brewer

Crossmatching Incompatible Microscope

Luke's Hospital and Plaza Infectious Disease, 4320 Wornall Road, Suite 440, Kansas City, MO 64111, USA The potential therapeutic approaches for human herpesvirus-6 (HHV-6) infections include antiviral therapy and immune therapies. Several experimental therapy approaches have possible benefits for such infection based on theoretical grounds as well as clinical studies. These therapies may alter viral infection via immune-mediated mechanisms, which relate to...

DRESS and HHV6 the first reports

Interestingly, all of the clinical and biological manifestations described in the DRESS are observed in some viral infection and especially HHV-6 infection. In 1993, Akashi et al. reported a severe infectious mononucleosis-like syndrome and primary HHV-6 infection in an adult (Akashi et al., 1993). A 43-year-old man was admitted with high fever, generalized exanthe-matic eruption followed by an exfoliative dermatitis, lymphadenopathy, atypical lymphocytes,...

Reactivation transplantation Solid organ transplant

In 1992, Yoshikawa first published that 14 of kidney transplant recipients developed HHV-6 viremia in the first 2-4 weeks posttransplant and 55 showed an increase in anti-HHV-6 antibody titer in the first 3 months (Yoshikawa et al., 1992). Since then, Singh and Carrigan (1996), Singh and Patterson (2000), Ljung-man (2002), and Lautenschlager et al. (2000) have reported HHV-6 as an emerging pathogen in solid organ transplantation. HHV-6 is expressed in the early weeks posttransplant, often...

Proposed pathogenic model of CFS

Human Fatigue Model

One etiologic model of CFS integrates genetic predisposition, immune perturbation, viral reactivation, and autonomic and immunoregulatory dysfunction to produce the symptom complex of CFS (Fig. 1). A persistent viral infection is one potential Fig. 1 Proposed model of chronic fatigue syndrome etiology, including the potential role of Fig. 1 Proposed model of chronic fatigue syndrome etiology, including the potential role of pathogenetic cofactor in this model. Immune activation (due to viral...

Current immunological tools

Although lymphoproliferation (LPA) has remained largely an immunological tool for the research laboratory, there are now a variety of new methodologies that do not require use of radioactive materials or the prolonged incubation times of LPA. These include flow cytometry assays to quantify subsets of circulating cells based on cell surface characteristics, ELISPOT to assess expression of cytokines, and newer cytokine genotype microarray methodologies. Genotype microarray technologies offer...

Ultrastructure and Assembly of Human Herpesvirus6 HHV6

Ultrastructure Herpesvirus

Stoopsa, Gerhard R.F. Kruegera,b aDepartment of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston Medical School, Houston, TX 77030, USA bDepartment of Anatomy II, The University of Cologne, Cologne 50924, Germany Human herpesvirus-6 HHV-6 is a ubiquitous member of the betaherpesvirus subfamily of the Herpesviridae family. The HHV-6 genome is arranged colinearly and codes for approximately 67 of proteins in common with human...