Reactivation of human herpesviruses 6 and 7 in Kawasaki disease

Abstract

Objectives: Kawasaki disease (KD) is one of the most common childhood vasculitides. Some serological studies have suggested an etiological relationship between KD and human herpesvirus (HHV)-6 or HHV-7. However, primary or reactivated HHV-6 and -7 has not been fully investigated in patients with KD.

Methods: Twenty-three patients with KD were prospectively enrolled in this study. Peripheral blood was collected in the acute and convalescence phases, and HHV-6 and -7 viral loads were measured by real-time PCR.

Results: In the acute phase, HHV-6 and -7 DNA was detected in 7 (30%) patients each, compared to 13 (57%) and 9 (39%) patients in the convalescence phase, respectively. HHV-6 and -7 DNA loads were significantly higher in the convalescence phase than in the acute phase. Significant increases in HHV-6 and -7 DNA loads were not observed in disease control patients. Taking into account HHV-6 and -7 serostatus, reactivation of HHV-6 and -7 was observed in 7 and 9 patients, respectively. KD patients with HHV-6 reactivation showed higher C-reactive protein levels and more frequently required steroid therapies than patients without reactivation.

Conclusion: HHV-6 and -7 reactivation is frequent in KD patients. HHV-6 reactivation might exacerbate the severity of KD.     

Tropism of human herpesvirus 8 for peripheral blood lymphocytes in patients with Castleman's disease

Multicentric Castleman's disease (MCD), also called multicentric angiofollicular lymphoid hyperplasia, is a systemic lymphoproliferative disorder causing fever, lymphadenopathy and splenomegaly. Recently, Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) DNA sequences have been detected in cases of MCD. We examined HHV-8 DNA sequences in the peripheral blood mononuclear cells (PBMCs) of two HIV-negative patients with MCD and in PBMCs and the lymph node of a HIV-negative patient with localized Castleman's disease (LCD) by the polymerase chain reaction. The novel sequences were detected in all DNA samples. Furthermore, the sequences were detected in only the CD19⁺ B-lymphocyte fraction of the patient with LCD as previously reported. However, the sequences were detected in CD19⁺ B-lymphocyte and CD2⁺ T-lymphocyte fractions of two patients with MCD. These results suggest that HHV-8 has tropisms for both B lymphocytes and T lymphocytes in Castleman's disease.     

Antibodies against human herpesvirus 8 in South African renal transplant recipients and blood donors

OBJECTIVE: To examine the seroprevalence of human herpesvirus 8 (HHV-8) antibodies in a selected group of renal transplant recipients and blood donors, in relation to various socio-demographic variables. SUBJECTS: Anonymised serum samples were obtained from 306 black donors attending blood donations at the SA National Blood Transfusion Service, Johannesburg, and 430 recipients of renal transplants at Johannesburg General Hospital, from 1998 to 1999. METHODOLOGY: Serum samples were tested by indirect immunofluorescence assay to detect IgG antibodies against HHV-8. Crude and adjusted seroprevalence, and odds ratios were calculated to examine the relationship between antibodies to HHV-8 and age, sex, population, and risk group. Results: Adjusted HHV-8 seroprevalence at 'medium to high' antibody titres (at least 1:51,200) increased with age, from 2% (age 15-24; 95% CI=0.7-5.2) to 10% (age 45+; 95% CI=6.3-15.2). Whites had the lowest % adjusted seroprevalence (1.8; 95% CI:0.8-4.2), followed by blacks (7.4; 95% CI=5.1-10.8), Asians/Indians (9.5; 95% CI=3.6-22.9), and individuals of mixed race (12.5; 95% CI=4.5-30.2). Seroprevalence was not related to gender, or to occupation of blood donors. HHV-8 seroprevalence did not differ significantly between first-time blood donors, repeat donors, and transplant recipients (P=0.49). Transplant recipients had a greater proportion of persons with high HHV-8 antibody intensity; however, this difference was statistically not significant (P=0.08). CONCLUSIONS: Blood donors and renal transplant patients had relatively high HHV-8 antibody titres. Given the strong association between HHV-8 seropostivity and the risk of developing Kaposi's sarcoma, it may be prudent in settings where HHV-8 seroprevalence is high to screen for HHV-8 in donated blood used for these immunocompromised individuals.     

Human herpesvirus 8-associated multicentric Castleman disease in a patient with advanced HIV infection: A case report

Rational:Multicentric Castleman disease (MCD) is a nonclonal lymphoproliferative disorder that is rarely reported from Southeast Asian countries. Here, we report a case of human herpesvirus 8 (HHV-8)-associated MCD in a patient with advanced human immunodeficiency virus (HIV) infection who presented with prolonged intermittent fever, urticarial rash, hepatosplenomegaly, and generalized lymphadenopathy.Patient concerns:A 34-year-old man with advanced HIV infection who was in good compliance with his antiretroviral treatment regimen presented with intermittent fever, weight loss, marked hepatosplenomegaly, and generalized lymphadenopathy. Recurrent symptoms of high-grade fever, abdominal discomfort, pancytopenia, and high C-reactive protein level occurred for 16 months.Diagnoses:Histopathological findings of left inguinal lymph node revealed diffuse effacement of lymph node architecture with coexpression of HHV-8 latency-associated nuclear antigen 1 from immunohistochemical staining. The HHV-8 viral load was 335,391 copies/mL.Interventions:The patient was treated initially with one dose of intravenous rituximab (375 mg/m²) followed by subcutaneous rituximab (1400 mg) weekly for 5 weeks.Outcomes:The patient''s recurrent systemic symptoms subsided dramatically, and he has now been in remission for almost two years.Lessons:HHV8-associated MCD remains a diagnostic challenge in advanced HIV disease and should be suspected in those with recurrent flares of systemic inflammatory symptoms. Lymph node histopathology is essential for diagnosis and for excluding clonal malignancy. HHV-8 viral load is also useful for diagnosis and for monitoring disease activity.     

Durable remission by sobuzoxane in an hiv-seronegative patient with human herpesvirus 8-negative primary effusion lymphoma

Primary effusion lymphoma (PEL) is recognized as a unique clinicopathological entity associated with human herpesvirus 8 (HHV-8), and it occurs almost exclusively in human immunodeficiency virus (HIV)-infected individuals. In the majority of PEL cases, Epstein-Barr virus (EBV) has been found in the tumor cells as well. We describe here an elderly HIV seronegative female patient with PEL in the pleura and pericardium not associated with HHV-8 or EBV. Cytologic examinations of the pleural effusion revealed large lymphoma cells with immunophenotypes positive for CD8, CD10, CD19, CD20, CD22, CD24, CD45, and HLA-DR but negative for CD30 and surface immunoglobulin. Chromosome analysis showed complicated abnormalities including add(3)(q27). Immunoglobulin gene rearrangement was detected by Southern blotting; however, c-myc, Bcl-2, and Bcl-6 genes were not rearranged. The patient was treated with a modified CHOP (cyclophosphamide, hydroxydoxorubicin, oncovine, and prednisolone) regimen, and achieved remission. Recurrence of PEL in the pericardium as effusion lymphoma was found 3 months after the discontinuation of CHOP. After approximately 1 year of intermittent multiagent salvage therapy for pericardial recurrences, a treatment that resulted in a partial response, 3 cycles of monotherapy with sobuzoxane were administered. At the time of this report the patient had been free from PEL for more than 18 months without chemotherapy.     

Integration of human herpesvirus 6 in a Burkitt's lymphoma cell line

Human herpesvirus 6 (HHV-6) genome has been found in several human lymphoid malignancies, but configuration of the HHV-6 genome has not been well delineated. We established the HHV-6-positive, Epstein-Barr virus-negative Burkitt's lymphoma cell line Katata. In this study we investigated the status of the HHV-6 genome in Katata cells. Neither linear nor circular HHV-6 DNA was detected by Gardella gel analysis. The fluorescence in situ hybridization technique enabled us to directly visualize the integrated HHV-6 DNA at the single-cell level. Only one integrated site of viral DNA was detected in metaphase chromosomes and it was preferentially located at the long arm of chromosome 22 (22q13). Treatment of the cells with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or with calcium ionophore A23187 led to induction of the HHV-6 immediate-early gene as well as the late gene. Sodium n-butyrate also gave rise to expression of the HHV-6 genes. The TPA inducibility was synergistically enhanced when combined with A23187 or n-butyrate. Our study provides, for the first time, an in vitro model system of latent HHV-6 infection whose genome is integrated into host DNA of lymphoma cells.     

Deconstructing the liquid architecture of human herpesvirus 8 diseases

Human herpesvirus 8 (HHV-8), also called Kaposi sarcoma herspesvirus (KSHV), causes several human tumours, which may be associated with systemic inflammation and body cavity effusions, including a form of multicentric Castleman disease (MCD) and a novel inflammatory syndrome, KSHV inflammatory cytokine syndrome (KICS). In this issue, Zhou et al. demonstrate that HHV-8-infected lambda-restricted plasmablasts can be detected in these effusions and can be used to distinguish MCD from other HHV-8 tumours as well as to categorise KICS into distinct clinicopathological groups. These findings open a path to an integrated clinicopathological approach to HHV-8-associated inflammatory diseases and may have clinical implications. Commentary on: Zhou et al. A novel approach for characterisation of KSHV-associated multicentric Castleman disease from effusions. Br J Haematol 2023;200:462-475.     

Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi's sarcoma

Post-transplantation lymphoproliferative disorders (PTLDs) and Kaposi's sarcoma (KS) are immunosuppression-related tumours developing in solid organ transplant patients. Although the Epstein-Barr virus (EBV) is detected in the majority of the PTLDs during the first year after transplantation, the proportion of EBV-negative PTLDs has increased in recent years. We report a case of a 17-year-old man who developed severe immune haemolytic anaemia, KS and human herpesvirus 8 (HHV-8)-associated, polymorphic-type PTLD 9 months after allogeneic renal transplantation from his HHV-8-seropositive father. It is suggested that: (i) HHV-8 may be associated with EBV-negative, polymorphous-type PTLD occurring less than 1 year after transplantation, and (ii) PTLD may be listed among other tumours, including KS, Castleman's disease and primary effusion lymphoma (PEL), that are related to HHV-8 infection.     

Prevalences of human herpesvirus 6 and human herpesvirus 7 in normal Thai population

Prevalences of human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) DNA were investigated in normal Thai population. Peripheral blood mononuclear cells (PBMC) and saliva were collected from 238 healthy adults in five provinces which might be a representative of each part of the country, and 120 normal children in one province. Prevalences of HHV-6 DNA PBMC were 45.5-74.3% in adults and 78.3% in children, and in saliva, very low prevalences were detected; 5.7-8.6% in adults and 15.0% in children, respectively. Additionally, all HHV-6 DNA detected in this study were variant B. Comparingly to those of HHV-7 DNA, the prevalences were significantly higher than those of HHV-6, ie, 82.9-91.4% in PBMC of adults, 85% in PBMC of children, 84.8-89.0% in saliva of adults and 92.5% in saliva of children. HHV-6 and HHV-7 isolation from saliva specimens were also performed. No HHV-6 could be isolated from any samples, whereas, in the present study, HHV-7 could be isolated as 90.0% from children and as 20.0-54.5% from adults.     

Human herpesvirus 6A active infection in patients with autoimmune Hashimoto's thyroiditis

BackgroundHypothyroidism due to Hashimoto's thyroiditis (HT) is the commonest autoimmune endocrine illness in which antibodies against thyroid organ result in inflammation. The disease has a complex etiology that involves genetic and environmental influences. Viral infections may be involved in triggering of the disease as their molecular mimicry enhance autoimmune responses. Human herpesvirus-6 (HHV-6) is recognized for its contribution to some autoimmune diseases.ObjectiveIn the current study, the prevalence of HHV-6 active infection in patients with HT and with non-autoimmune thyroid disorders were compared with patients with euthyroidism. In addition, a correlation between presence of HHV-6 infections and HT was investigated.MethodsA total of 151 patients with clinically and laboratory confirmed HT, 59 patients with non-autoimmune thyroid disorders, and 32 patients with normal thyroid function were included in the study. For further confirmation of HT disease, all the precipitants were tested for anti-thyroid peroxidase (TPO), and anti-thyroglobulin (TG) antibodies. For detection of both HHV-6 types A and B, nested PCR and restriction enzyme digestion were used. HHV-6 DNA positive samples were further investigated by DNA sequencing analysis.ResultsHHV-6A DNA was found in serum sample of 57 out of 151 patients (38%) with HT, which was significantly more often than in patients with non-autoimmune thyroid disorders (p = 0.001). However, HHV-6 DNA was not detected in serum samples of euthyroid subjects.ConclusionsThe results support a possible role for active HHV-6A infection, demonstrated by the presence of HHV-6 DNA in sera, in the development of HT.     

Detection of human herpesvirus 6 and JC virus in progressive multifocal leukoencephalopathy complicating follicular lymphoma

Progressive multifocal leukoencephalopathy (PML), a demyelinating infectious disease caused by JC virus (JCV), occurs almost exclusively in immunocompromised patients usually with malignant diseases. We report here a Japanese female with follicular lymphoma who subsequently developed PML. In addition to JCV, human herpesvirus 6 (HHV-6) was detected in the affected brain lesions of the patient by polymerase chain reaction and by in situ hybridization. HHV-6, recognized as a neurotropic virus, is known to be reactivated during immunosuppression and can cause fatal complications such as encephalitis/encephalopathy. It is likely that impaired immunity associated with lymphoma and the additional immunosuppression following cytopenia-inducing chemotherapies predisposed the patient to reactivated HHV-6 infection. Although it remains to be clarified whether HHV-6 plays an important role as a co-agent with JCV in causing demyelination of the brain, our observation alerts physicians to the possible association of HHV-6 with the pathogenesis of PML.     

Danish patients with untreated multiple myeloma do not harbour human herpesvirus 8

The role of human herpesvirus 8 (HHV-8) in multiple myeloma (MM) remains controversial. We examined 15 Danish MM patients before cytoreductive therapy. Mononuclear cells isolated from peripheral blood and bone marrow aspirates, as well as long-term cultured bone marrow stromal cells, were assayed for the presence of HHV-8 DNA. All material was tested by three simple unnested polymerase chain reaction (PCR) assays (amplifying regions of ORF26, ORFK1 and ORF75) and two nested PCR assays (amplifying regions of ORF26). HHV-8 was not demonstrated in any of the samples. Our findings do not suggest an association between HHV-8 and MM in the Danish population.     

Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus.

An independent strain (JI) of human herpesvirus 7 (HHV-7) was isolated from a patient with chronic fatigue syndrome (CFS). No significant association could be established by seroepidemiology between HHV-7 and CFS. HHV-7 is a T-lymphotropic virus, infecting CD4+ and CD8+ primary lymphocytes. HHV-7 can also infect SUP-T1, an immature T-cell line, with variable success. Southern blot analysis with DNA probes scanning 58.8% of the human herpesvirus 6 (HHV-6) genome and hybridizing to all HHV-6 strains tested so far revealed homology to HHV-7 with only 37.4% of the total probe length. HHV-7 contains the GGGTTA repetitive sequence, as do HHV-6 and Marek's disease chicken herpesvirus. DNA sequencing of a 186-base-pair fragment of HHV-7(JI) revealed an identity with HHV-6 and human cytomegalovirus of 57.5% and 36%, respectively. Oligonucleotide primers derived from this sequence (HV7/HV8, HV10/HV11) amplified HHV-7 DNA only and did not amplify DNA from other human herpesviruses, including 12 different HHV-6 strains. Southern blot analysis with the p43L3 probe containing the 186-base-pair HHV-7 DNA fragment hybridized to HHV-7 DNA only. The molecular divergence between human cytomegalovirus, on the one hand, and HHV-6 and HHV-7, on the other, is greater than between HHV-6 and HHV-7, which, in turn, is greater than the difference between HHV-6 strains. This study supports the classification of HHV-7 as an additional member of the human beta-herpesviruses.     

Human herpesvirus type 7 in Hodgkin's disease

Several lines of evidence have pointed to the involvement of a viral agent in the pathogenesis of Hodgkin's disease (HD). Therefore we investigated the presence of human herpesvirus type 7 (HHV-7) in 53 cases of HD by polymerase chain reaction (PCR), DNA in situ hybridization (ISH) and immunohistochemistry. HHV-7 DNA was frequently detected (68% of the cases) in HD biopsies by PCR independently of the histological type, whereas only 32% ( P  < 0.05) of positive cases were found in 19 reactive lymph nodes. However, by applying the quantitative PCR technique, the majority of the samples showed a low level of viral load. Moreover, ISH for HHV-7 DNA was positive in a low number of small T lymphocytes and consistently negative in Hodgkin and Reed-Sternberg (HRS) cells, which appeared negative for HHV-7 also at immunohistochemistry.   These results indicate that the high frequency of HHV-7 infection in HD: (i) is probably non-productive, (ii) mainly involves small lymphocytes belonging to the T-lineage, and (iii) is probably due to the recruitment of non-malignant reactive cells in HD tissue.     

Caregiver burden and fatigue in caregivers of people with dementia: Measuring human herpesvirus (HHV)-6 and -7 DNA levels in saliva

PurposeWe examined chronic fatigue, which has not been investigated in detail, in family caregivers for people with dementia.Methods and materialsForty-four community-dwelling family caregivers (the caregiver group: CG) and 50 elderly control participants (the non-caregiver group: NCG) participated in this study. We measured salivary human herpesvirus (HHV)-6 and -7 DNA levels and the Chalder fatigue scale (CFS) to assess levels of fatigue; we also measured the Center for Epidemiologic Studies-Depression Scale, Physical Activity Scale for the Elderly, Zarit Caregiver Burden Interview, Mini-Mental State Examination, Assessment of Motor and Process Skills, and Dementia Behavior Disturbance Scale.ResultsFor CG, the salivary HHV-6 DNA levels and CFS scores were significantly higher than those in NCG. The salivary HHV-6 DNA levels in CG were significantly correlated with depressive symptoms, the cognitive function of the patients, and the activities of daily living/instrumental activities of daily living (ADL/IADL) abilities of the patients. The CFS scores in CG significantly correlated with caregiver burden, depression symptoms, leisure physical activity, the number of other family caregivers, and the hours spent for caregiving per week, as well as with behavior disturbances and ADL/IADL abilities.ConclusionsThe salivary HHV-6 DNA levels may be added as a new biomarker for caregiver exhaustion. We concluded that fatigue assessments should be performed by not only a questionnaire, such as the CFS, but also by a biomarker search, such as HHV-6, when estimating the caregiver burden for family caregivers of people with dementia.     

High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients

The aim of this study was to correlate human herpesvirus (HHV)-6 viral load with clinical symptoms in allogeneic stem cell transplant (SCT) patients. Seventy-four patients were monitored during the first 3 months after SCT using a qualitative polymerase chain reaction (PCR) for HHV-6 DNA. HHV-6 was detected in 181 out of 494 samples (36%) from 58 (78%) patients. These 181 samples were analysed using a quantitative competitive PCR. DNA could be quantified from 146 out of 181 samples (80.6%). The HHV-6 viral load was highest at 4 weeks compared with 8 weeks (P < 0.001) and 12 weeks (P = 0.01) after SCT. Three patients had HHV-6 encephalitis and one patient had hepatitis. The HHV-6 DNA levels were higher in patients with HHV-6 than in those without HHV-6 (P = 0.01). Patients who received grafts from unrelated or HLA-mismatched family donors had significantly higher HHV-6 DNA levels than patients who received grafts from matched sibling donors (P < 0.001). In a multiple regression model, unrelated donor grafts (P < 0.001) and use of intravenous immunoglobulin prophylaxis (P = 0.04) influenced HHV-6 DNA levels. HHV-6 viral load was significantly correlated with delayed platelet engraftment in both univariate (P < 0.01) and multivariate analysis, and to the number of platelet transfusions.     

Human herpesvirus 6 positive Reed-Sternberg cells in nodular sclerosis Hodgkin lymphoma

Classical Hodgkin lymphoma (HL) exhibits a bi-modal age distribution that suggests an infectious aetiology. However, most cases of nodular sclerosis HL (NSHL) are Epstein-Barr virus (EBV) negative (60-90%). Previous studies regarding human herpesvirus 6 (HHV-6) positivity of HL have led to conflicting results. In order to clarify this situation, we examined NSHL biopsies for the presence and distribution of HHV-6 by immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). PCR identified HHV-6 DNA in 86% of NSHL cases. As HHV-6 DNA was also identified in most cases of reactive lymphoid hyperplasia, we sought to localize the virus to specific cells by IHC, which detected HHV-6 in Reed-Sternberg (RS) cells of nearly half (48%) of NSHL cases. Dual CD30/HHV-6 immunostaining confirmed HHV-6 immunoreactivity in CD30+ RS cells, and HHV-6 PCR positivity was confirmed in laser capture microdissection-isolated CD30+ RS cells. FISH demonstrated multiple copies of HHV-6 genome in scattered cells. In contrast, EBV+ RS cells were identified in only 24% of the cases. HHV-6+ cases trended toward a younger age than EBV+ cases. These results conclusively demonstrate that RS cells in many cases of NSHL are HHV-6 positive, and suggest that HHV-6 may play a role in NSHL pathogenesis, particularly in younger patients with EBV-negative disease.     

Variation of human herpesvirus 7 shedding in saliva

Sequential analysis of human herpesvirus 7 (HHV-7) shedding in saliva obtained from healthy adults was performed for 6 months; virus was isolated in 92 (34.1%) of the 270 saliva samples obtained. Frequency of HHV-7 shedding in serially obtained saliva samples varied among subjects. Associations between frequency of HHV-7 shedding and age, sex, and virus antibody titer were analyzed, and, although sex was not associated with frequency of shedding, young age (P=.031) and low antibody titer (P=.006) were correlated with frequent viral shedding (5 or 6 times/6 months).     

Human Herpesvirus 8 in Australia: DNAemia and Cumulative Exposure in Blood Donors

Human herpesvirus 8 (HHV-8), the causative agent of Kaposi’s sarcoma, multicentric Castleman’s disease and primary effusion lymphoma, predominantly manifests in immunocompromised individuals. However, infection in immunocompetent individuals does occur. The prevalence of HHV-8 exposure in blood donors from non-endemic countries ranges between 1.2% and 7.3%. Nothing was known about the prevalence in Australian blood donors. Therefore, this study investigated the active and cumulative exposure of HHV-8 in this cohort. Plasma samples (n = 480) were collected from eastern Australian blood donors and were tested for HHV-8 DNA by qPCR, and for HHV-8 antibodies by two different ELISAs. Samples initially positive on either ELISA were retested in duplicate on both, and on a mock-coated ELISA. Any samples positive two or three out of the three times tested on at least one ELISA, and repeat negative on the mock-coated ELISA, were assigned as repeat positive. None of the 480 samples tested contained HHV-8 DNA. Serological testing revealed 28 samples (5.83%; 95% CI: 3.74–7.93%) had antibodies to HHV-8. There was no difference (p > 0.05) in seropositivity between sex or with increasing age. This is the first study to show serological evidence of cumulative HHV-8 exposure and no HHV-8 DNAemia within a select blood donor population in Australia. Our molecular and serological data is consistent with published results for blood donors residing in HHV-8 non-endemic countries, which shows the prevalence to be very low.     

Multiple sclerosis and human herpesvirus 6

Background: A possible but as yet unproven relationship has been proposed between the onset or persistence of multiple sclerosis (MS) symptoms and herpesviruses, including, most recently, human herpesvirus 6 (HHV-6). A study was conducted to investigate the presence of HHV-6 DNA and the synthesis of antibodies against HHV-6, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in serum and cerebrospinal fluid (CSF) of patients with MS. Materials and Methods: PCR and ElISA were used to detect HHV-6 DNA and specific antibodies against HHV-6, CMV and EBV in 211 samples (139 sera and 72 CSF). There were three groups of samples: group I, paired samples of serum and CSF from 41 MS patients; group II, paired samples of serum and CSF from 31 patients with neurological diseases other than MS (OND); group III, 67 serum samples from 27 different MS patients undergoing serologic follow-up. Results: No HHV-6 DNA was found in any sample. Group I sera showed elevated anti-HHV-6 IgG and IgA levels. In group II, anti-CMV IgG was detected in one CSF sample and anti-HHV-6 IgM in one serum sample. Group III sera showed high concentrations of anti-HHV-6 IgG, IgA and IgM. Conclusion: Given the clinical implications of the presence of antibodies against HHV-6 in MS patients, a viral reactivation cannot be excluded as an environmental factor. Received: April 5, 2001 · Revision accepted: January 22, 2002