Case of drug-induced hypersensitivity syndrome due to lamotrigine: demonstration of sequential reactivation of herpesviruses

Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe multiorgan disorder. The reactivation of human herpesvirus-6 (HHV-6) and other human herpesviruses has been reported to be associated with its pathogenesis. We herein report a case of 14-year-old female who developed DIHS during the treatment with lamotrigine, a novel antiepileptic drug. She initially presented with fever, skin rash, cervical lymphadenopathy, leukocytosis with eosinophilia and atypical lymphocytosis, liver dysfunction and hypogammaglobulinemia. Discontinuation of the drug and administration of prednisolone led to improvement;however, tapering of prednisolone and administration of midazolam and ketamine thereafter triggered clinical deterioration. She subsequently developed hyperthyroidism followed by hypothyroidism. Herpesviral loads were determined in her peripheral blood by real-time PCR during the course of the treatment, and sequential reactivation of Epstein-Barr virus (EBV), HHV-6 and cytomegalovirus was demonstrated. EBV viremia was detected throughout the course, except for a short period when HHV-6 viremia was at the peak. HHV-6 viremia developed after the secondary deterioration. Cytomegalovirus viremia appeared transiently before the hyperthyroidic state reversed and became hypothyroidic. Although this syndrome should be regarded as a systemic reaction induced by a complex interplay among herpesviruses and the immune responses against viral infections and drugs, it remains unknown how such a sequential reactivation is related to the pathogenesis of the condition.     

Limbic encephalitis associated with drug-induced hypersensitivity syndrome due to phenobarbital--a case report]

A 68-year-old man was diagnosed as drug-induced hypersensitivity syndrome (DIHS) with erythema and liver dysfunction three weeks after an administration of phenobarbital. Three weeks after the appearance of skin eruptions, the patient developed disturbed consciousness and status epilepticus. MRI findings revealed bilateral symmetrical abnormalities localized in the amygdala, hippocampi, parahippocampal gyri, and insula regions, which showed high intensities on diffusion weighted images and decreased apparent diffusion coefficient (ADC) values on an ADC map. We considered that the MRI abnormalities were indicative of cytotoxic edema. Increased serum anti-human herpesvirus 6 (HHV-6) IgG antibody titer and presence of HHV-6 DNA in peripheral blood, revealed by polymerase chain reaction (PCR) analysis, suggested reactivation of HHV-6. However, PCR analysis performed with DNA extracted from the CSF was negative for HHV-6. We concluded that limbic encephalitis in the present case might have been caused by an autoimmune inflammatory mechanism associated with drug-induced hypersensitivity syndrome, as well as a direct infection of HHV-6 to the central nervous system.     

Anti-viral properties of interferon beta treatment in patients with multiple sclerosis

Viral infections are potentially associated with the etiology and pathogenesis of multiple sclerosis (MS). It has been speculated that the treatment efficacy of interferon beta (IFN beta) in MS may relate to its anti-viral properties. The study was undertaken to evaluate the in vivo anti-viral effects of IFN beta-1a in patients with MS. Human herpesvirus-6 (HHV-6) was studied as an example for being a latent neurotropic virus. IFN beta used at concentrations of approximately 0.5 microg/ml was shown to significantly reduce in vitro HHV-6 replication in a susceptible T-cell line. Sera derived from 23 MS patients treated with IFN beta-1a were examined for serum cell-free DNA of HHV-6 as an indicator for viral replication and the reactivity of IgM antibodies to a recombinant HHV-6 virion protein containing a known immunoreactive region. The results were compared with those of control sera obtained from untreated MS (n=29) and healthy individuals (n=21). The findings indicated that IFN beta treatment significantly reduced HHV-6 replication as evident by decreased cell-free DNA in treated MS specimens. The results correlated with decreased IgM reactivity to the HHV-6 antigen in treated MS patients compared to untreated controls, suggesting reduced exposure to HHV-6. The findings were confirmed in paired sera obtained from seven MS patients before and after the treatment The study provides new evidence indicating that IFN beta has potent in vivo anti-viral effects that may contribute to the treatment efficacy in MS.     

Efficacy of antiviral compounds in human herpesvirus-6-infected glial cells

The beta-herpesvirus human herpesvirus-6 (HHV-6) is becoming increasingly recognized as an important pathogen in immunocompromised patients, particularly in post bone marrow transplant (BMT). Reactivation of latent HHV-6 resulting in encephalitis has been reported in BMT and stem cell transplant (SCT) patients. The development of HHV-6 encephalitis can be a fatal complication, the frequency of which is increasing likely due to improved diagnosis with quantitative polymerase chain reaction (PCR) of cerebrospinal fluid. There are currently no antiviral compounds approved for HHV-6, nor have any controlled clinical trials been conducted. The frequency and severity of HHV-6 encephalitis in both immunocompetent and immunocompromised patients necessitates studies on the usefulness of currently available anti-viral compounds. The authors compared the antiviral efficacy of four drugs currently used for cytomegalovirus (CMV) infection, a beta-herpesvirus sharing homology with HHV-6. In HHV-6A- and HHV-6B-infected T cells, acyclovir, ganciclovir, foscarnet, and cidofovir exhibited antiviral activity consistent with that published in other studies. In HHV-6-infected human astrocytes (U251), however, only foscarnet and cidofovir exhibited antiviral activity and this effect was restricted to infection with HHV-6 variant A. In pathological brain sections from patients with neurological disorders such as multiple sclerosis and epilepsy, HHV-6 has been localized to glial cells. Determination of antiviral activity in human glial fibrillary acidic protein (GFAP)-positive astrocytes of currently used antiviral compounds is essential for potential treatment of HHV-6 and neurological disorders. Our data highlight the necessity for further study of antiviral compound in HHV-6-infected glial cells as well as the development of more selective compounds for HHV-6.     

Beta-interferon treatment reduces human herpesvirus-6 viral load in multiple sclerosis relapses but not in remission

To determine whether the DNA prevalence of human herpesvirus-6 (HHV-6), the viral load and the prevalence of both HHV-6 variants in relapsing-remitting multiple sclerosis (RRMS) patients in exacerbation are altered by beta-interferon (IFN-beta) treatment, in comparison with RRMS patients in remission, we analyzed HHV-6 (A and B) genomes in 189 serum samples by quantitative real-time polymerase chain reaction: 105 of the RRMS patients were receiving IFN-beta treatment (48 in exacerbation) and 84 were untreated (36 in relapse). The results were as follows. (1) Prevalence decrease because of IFN-beta treatment was not significant: 25% of RRMS patients in relapse vs. 15.9% in remission (p = 0.45). (2) Viral load was twice as much in untreated patients in relapse than in treated ones. (3) We only found variant A. Since IFN-beta treatment is able to significantly reduce HHV-6 viral load in RRMS patients in relapse, but not in remission, we suggest a role for HHV-6 in the pathogenesis of multiple sclerosis exacerbations and an antiviral role for IFN-beta treatment in RRMS.     

Detection of human herpesvirus 6 variant A in peripheral blood mononuclear cells from multiple sclerosis patients

Several authors report that human herpesvirus 6 (HHV-6) variants have different epidemiologies, in vivo tropism and pathogenic potentials. However, it is not well known what pathogenic roles its neurotropism might have in the variant type. As some active plaques of multiple sclerosis (MS) brain tissue harbor HHV-6 DNA divergent from the prototype virus, the possibility that the variant strain may play a role in the pathogenesis of MS has been suggested. Therefore, we tried to investigate the role of HHV-6 variants in the pathogenesis of MS. As HHV-6 is predominantly a T-cell-tropic virus, we examined HHV-6 DNA sequences in peripheral blood mononuclear cells (PBMC) from 34 MS patients, 6 with idiopathic transverse myelitis, 2 with optic neuritis and 20 healthy controls. Nested polymerase chain reaction was used to detect the HHV-6 genome. To discern HHV-6 variants A and B, amplification products were digested by restriction enzyme. We found that 7 of 34 MS patients and 2 of 6 patients with idiopathic transverse myelitis had the HHV-6 genome. On the contrary, there was no HHV-6 genome in the control group. All genomic sequences were of HHV-6 variant A (HHV-6A). Our results suggest that the detection of HHV-6A in the PBMC of patients with MS may raise the possibility of a relationship between latent HHV-6A infection and the pathogenesis of MS.     

Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity

OBJECTIVE: To assess the presence of Epstein-Barr virus (EBV) and human herpesvirus 6B (HHV-6B) DNA in saliva and plasma from multiple sclerosis (MS) patients enrolled in a randomized, double-blind, placebo-controlled valacyclovir treatment study. METHODS: DNA was prepared following ultracentrifugation of saliva and plasma. EBV and HHV-6B DNAs were determined by real-time polymerase chain reaction. RESULTS: EBV and HHV-6B DNAs were detected in 41% and 65% of saliva samples, respectively. In patients treated with valacyclovir, the percentage of saliva samples with EBV was significantly reduced (9%; P = 0.000017), whereas the frequency of HHV-6B positive samples was unchanged (57%; P = 0.38). Longitudinal studies demonstrated a time-dependent reduction in the frequency of saliva samples containing EBV following valacyclovir treatment. In contrast, plasma contained EBV and HHV-6B DNAs in 17% and 25% of the samples, respectively, and these numbers were not significantly reduced following valacylovir treatment (13% and 16%, respectively), nor were they different from those of healthy controls (6% and 39%, respectively). Patients with high disease activity had a significantly higher frequency of EBV (P = 0.018) and HHV-6B (P = 0.023) positive samples than did patients with low disease activity. The presence of EBV and HHV-6B was strongly correlated in plasma (P < 0.00000001), but not in saliva (P = 0.41). CONCLUSION: MS patients express EBV and HHV-6B in both saliva and plasma, but only the expression of EBV in saliva is significantly reduced following valacyclovir treatment. Although EBV and HHV-6B DNAs can be detected in plasma from healthy individuals, the co-expression of both these viruses in MS patients is highly significant and further associated with clinical activity. The observations of viral DNA in plasma are consistent with an underlying immunologic defect in MS.     

Baló's concentric sclerosis associated with primary human herpesvirus 6 infection

BACKGROUND: Baló's concentric sclerosis (BCS) is a demyelinating disorder believed to be a rare variant of multiple sclerosis (MS). Human herpesvirus 6 (HHV-6) is a highly neurotropic virus causing severe central nervous system (CNS) infections predominantly following reactivation of latent HHV-6 in immunocompromised individuals. Primary infection with HHV-6 usually occurs in early childhood manifesting as exanthema subitum. The clinical spectrum of primary infection in adolescents or adults has not yet been evaluated. Case report: A previously healthy 13 year old girl developed acute hemianopsia and anomia 5 days after an episode of fever and malaise of unknown origin. Cerebral MRI revealed three white matter lesions, one with ring-like contrast enhancement. Lumbar puncture showed mononuclear pleocytosis of 30 cells/microl, oligoclonal IgG, and a normal protein level. Follow up cerebral MRI scans revealed lamellar concentric hemispheric lesions characteristic of BCS. The first neurological symptoms of the patient coincided with primary HHV-6 CNS infection, diagnosed by a positive PCR test of the CSF together with seroconversion. Response to antiviral and corticosteroid treatment was only temporary, but immunoglobulin treatment has so far been followed by clinical stability for 30 months. CONCLUSIONS: To our knowledge, this is the first report both of an association between HHV-6 and BCS and of immunoglobulin treatment of BCS. A late primary infection with HHV-6 might be associated with BCS. Further studies in patients with this rare disease are needed to confirm this association and to evaluate the efficacy of antiviral and immunoglobulin treatment.     

Prevalence of herpesvirus DNA in MS patients and healthy blood donors

OBJECTIVES: The aim of this study is to determine the DNA prevalence of different members of Herpesviridae in multiple sclerosis (MS) patients and to describe the possible effect of beta-interferon treatment on such prevalence. MATERIAL AND METHODS: With a nested polymerase chain reaction (PCR) assay we have studied the DNA of the peripheral blood mononuclear cells (PBMCs) of 204 whole blood samples, [102 from patients with relapsing-remitting MS (RRMS), of which 62 were treated with beta-interferon, and 102 from healthy blood donors]. RESULTS: We only found a statistically significant difference for human herpesvirus type 6 (HHV-6) DNA prevalence (P < 0.0001): HHV-6 is 2.26 times more frequent in MS patients than in healthy donors. There was no difference in the HHV-6 prevalence between beta-interferon treated and untreated patients. CONCLUSION: 1. Among the herpesviruses, HHV-6 was the only one showing altered prevalence. This either indicates that HHV-6 is involved in the pathogenesis of MS, or it simply indicates that MS influences latency or reactivation of HHV-6 without any direct involvement of HHV-6 in the disease process of MS. 2. Treatment with beta-interferon does not make a difference on the DNA prevalence of the herpesviruses studied in our MS patients.     

Human herpesvirus type 6 indirectly enhances oligodendrocyte cell death

Accumulating evidence suggests that human herpesvirus type 6 (HHV-6) plays a pathogenic role in diseases of the central nervous system including multiple sclerosis (MS). Recent studies have indicated that HHV-6 DNA is detected with high frequency in MS lesions compared to normal-appearing white matter, implicating a role for HHV-6 in MS pathogenesis. It appears that T cells, which infiltrate into the brain in MS patients, and resident oligodendrocytes harbor HHV-6 virus in MS lesions. Because T cells infected with HHV-6 have elevated proinflammatory gene expression, we hypothesized that HHV-6 could be indirectly cytotoxic to glial cells, including oligodendrocytes. Supernatants from SupT1 cells infected with HHV-6 variant A (GS or U1102) or variant B (Z29) significantly reduced MO3.1 cell proliferation by 75% ± 10%, 78% ± 8% or 51% ±9%, respectively. HHV-6 viral supernatants (GS or U1102 or Z29) significantly increased MO3.1 or primary human oligodendrocyte precursor cells (OPCs) cell death, whereas primary human fetal astrocytes were not affected. Removal of HHV-6 virions or proteins by trypsin treatment from culture supernatants did not reverse the loss in oligodendrocyte proliferation or viability. Supernatants from HHV-6 GS or U1102 cultures were significantly more cytotoxic to MO3.1 cells or OPCs compared to supernatants from T cells infected with Z29. Dying oligodendrocytes did not have an apoptotic-like phenotype and toxicity was not inhibited by general inhibitor of apoptosis, ZVAD. Further, oligodendrocytes had minimal caspase-3 activation even in the presence of staurosporine, suggesting that cell death followed caspase-independent pathways. These results indicate that HHV-6 is indirectly cytotoxic to oligodendrocytes and that cell death is driven primarily by caspase-independent pathways.     

Interferon beta treatment: Bioavailability and antiviral activity in multiple sclerosis patients

Viral infections have been appointed as the main component of environmental susceptibility to multiple sclerosis (MS). Interferon beta is an immunomudulatory treatment that is able to modify the natural course of the disease; nonetheless, its mechanism of action in not well established yet. The objectives of the present study were (1) to evaluate the bioavailability of interferon beta through the measurement of the expression of myxovirus resistance protein (MxA), metalloproteinase 9 (MMP-9), and its inhibitor (TIMP-1); (2) to analyze its antiviral efficiency through the measurement of human herpesvirus-6 (HHV-6) prevalence; and (3) to correlate both parameters (bioavailability and antiviral efficiency) with the relapse rate in multiple sclerosis (MS) patients treated with interferon beta. Pairs of blood and serum samples were collected from 54 MS patients during five visits in 1 year: one before the start of the treatment and four during interferon beta treatment. Expression of MxA, MMP-9, and TIMP-1 was analyzed by quatitative real-time polymerase chain reaction (qRT-PCR) and HHV-6 genomes were detected by qPCR. The results showed a correlation between MxA and relapse rate (P = .014). MMP-9/TIMP-1 ratio was increased among the patients with relapses, and decreased among the relapse-free patients, although differences were not statistically significant. Furthermore, our results suggest a possible role for HHV-6 in MS, because 42.8% of patients with viral reactivations experienced at least one relapse versus 22.5% of patients without viral reactivations. Lastly, regarding the antiviral effectiveness of the interferon beta, the HHV-6 prevalence decreased from 58% to 36% in PBMCs and from 18.5% to 12.2% in sera; furthermore, a good correlation with the bioavailability of interferon beta was found, because patients with a decrease in HHV-6 prevalence had higher levels of MxA (P = .046, at the third month).     

Active human herpesvirus 6 infection in patients with multiple sclerosis

CONTEXT: Human herpesvirus 6 (HHV-6) has been linked with multiple sclerosis (MS). OBJECTIVES: To determine HHV-6 viral load in patients with MS, and to analyze separately its 2 variants, HHV-6A and HHV-6B. PATIENTS AND METHODS: We analyzed 149 blood and serum samples; 103 were from patients with relapsing-remitting MS (33 during an MS relapse and 70 during remission), and 46 were from healthy blood donors. To determine whether the HHV-6 genome and its variants were present, we analyzed viral DNA using quantitative real-time polymerase chain reaction, which has a sensitivity of 1 copy. RESULTS: We found HHV-6 DNA in the peripheral blood mononuclear cells of 53.4% of patients and 30.4% of healthy blood donors; HHV-6A was found in 20.4% of patients and 4.4% of controls, and HHV-6B was found in 33.0% vs 26.1%, respectively. Mean viral load in both groups was 7.4 copies of HHV-6 per microgram of DNA (range, 1-15 copies). Analysis of serum samples showed that none of the healthy blood donors were positive for HHV-6, although 14.6% of patients were positive for the virus, specifically the HHV-6A variant. There was no difference between patients during remission or relapse. Mean viral load was 26.3 copies/microg microgram of DNA (range, 1-86 copies). CONCLUSIONS: Despite the low viral load and the lack of clinical correlation, and given the biological characteristics of the virus, our results suggest that there was active HHV-6A infection in 14.6% of patients with MS. Further quantitative real-time polymerase chain reaction studies will help us understand the clinical significance of such a low viral load.     

Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children

In order to determine whether the newly discovered human herpesviruses (HHVs) are involved in multiple sclerosis (MS), we investigated by polymerase chain reaction the presence of specific deoxyribonucleic acid (DNA) sequences belonging to human herpesvirus 6 (HHV-6) and to human herpesvirus 8 (HHV-8), in the peripheral blood mononuclear cells (PBMCs), and in the brain and spinal cord plaques from MS patients. Normal adult and stillborn children’s brains were investigated as controls. PBMCs from 56 MS patients contained HHV-6 DNA in only 3 cases and in none were there HHV-8 sequences. The cerebral DNA from 5 MS patients was positive for HHV-8 and not for HHV-6 sequences, while the nervous tissue of one patient who died with neuromyelitis optica was positive for HHV-6 and negative for HHV-8. The brains of 4/8 adult controls were positive for HHV-6, as were 3/8 for HHV-8; none of the 7 stillborn children’s cerebral tissue contained HHV-6 sequences, while 2 contained HHV-8 DNA. Although these data do not support a hypothesis that there is a role for these two HHVs in the pathogenesis of MS, nevertheless it may be suggested that (1) the two viruses possess strong neurotropism and the central nervous system seems to be a reservoir for them (2) HHV-6 infection is probably not transmitted maternally, but is acquired later in infancy. Received: 6 February 1997 Received in revised form: 18 April 1997 Accepted: 18 April 1997     

The prevalence of human herpesvirus 6 in human sensory ganglia and its co-occurrence with alpha-herpesviruses

Human herpesvirus 6 (HHV-6) persists in the central nervous system, but its prevalence in the peripheral nervous system, a preferred latency site for herpesviruses, has not been studied. Using nested polymerase chain reaction (PCR), the authors determined the distribution of HHV-6 in human sensory ganglia. HHV-6 was present in 30% of trigeminal, 40% of geniculate, 25% of vestibular, and 55% of dorsal root ganglia. It co-occurred with alpha-herpesviruses (herpes simplex virus type 1 or varicella-zoster virus) in 91% of the ganglia. As HHV-6 positivity did not depend on the presence of inflammatory cells, known to harbor the virus, HHV-6 probably resides in the ganglia themselves.     

Human herpes virus-6 encephalitis causing severe anterograde amnesia associated with rituximab,azathioprine and prednisolone combination therapy for dermatomyositis

Human herpes virus-6 (HHV-6) reactivation is a well-recognised complication following haematological stem cell transplantation, but it is novel in the context of combination immunomodulatory therapy for autoimmune disease. We report a case of severe anterograde amnesia caused by HHV-6 encephalitis in a young female patient on rituximab, azathioprine and prednisolone for dermatomyositis (DM). The use of targeted biologic treatments for systemic autoimmune connective tissue diseases (CTDs) is increasing, particularly when refractory to conventional management. The anti-CD20 B cell depleting monoclonal antibody, rituximab is now increasingly used, often in combination with conventional immunomodulatory treatments, in certain autoimmune neurological conditions and systemic CTDs including DM. Physicians should be aware of the possibility of HHV-6 in those who develop encephalitis while CD20 B cell deplete, especially in the presence of additional immunomodulatory therapies. Prompt diagnosis and treatment of HHV-6 encephalitis with evidence-based anti-viral therapy may help reduce the extent of irreversible morbidity such as amnesia.     

Human herpesvirus 6 in cerebrospinal fluid of patients infected with HIV: frequency and clinical significance

The objective was to evaluate the frequency of human herpesvirus 6 (HHV-6) DNA detection in the CSF of patients infected with HIV and its relation to brain disease and systemic HHV-6 infection. Nested polymerase chain reaction (PCR) was used to analyse CSF samples from 365 consecutive HIV infected patients with neurological symptoms. When available, plasma and brain tissues from patients whose CSF was HHV-6 positive were also studied. HHV-6 was found in the CSF of eight of the 365 patients (2.2%): two had type A and four type B; the HHV-6 variant could not be defined in the remaining two. All eight patients had neurological symptoms and signs related to concomitant opportunistic brain diseases, including cytomegalovirus (CMV) encephalitis in five patients whose CSF was also positive for CMV-DNA. Opportunistic infections but no other unexplained lesions were also found in the brain of all of the four patients who underwent neuropathological examination. Both HHV-6 and CMV were also detected in the plasma of respectively five and seven of seven patients whose CSF was HHV-6 positive. In conclusion, HHV-6 type A or B DNA was infrequently found in the CSF of HIV infected patients, in association with both CMV brain infection and systemic HHV-6 replication. However, no certain relation between HHV-6 and brain disease was found.     

Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients

Several reports have suggested an association of human herpesvirus 6 (HHV-6) and multiple sclerosis (MS) based on immunohistochemical demonstration of HHV-6 antigens in inflammatory lesions, detection of increased HHV-6 specific serum antibody titers, and amplification of HHV-6 DNA from sera and cerebrospinal fluid of MS patients but not in controls. Characterization of the cellular immune response of MS patients to HHV-6 may further clarify the role of HHV-6 in MS and provide insight into the pathogenesis of this immune-mediated disease. We have compared lymphoproliferative responses to HHV-6A (U1102)-, HHV-6B (Z29)-, and HHV-7 (H7SB)-infected cell lysates in healthy controls and patients with MS. Most healthy controls (71%) proliferated to HHV-6B lysate, and fewer (33%) responded to the HHV-6A lysate. In contrast, 67% of MS patients had a lymphoproliferative response to HHV-6A, which is a significant increase in comparison with healthy controls. A similar frequency of lymphoproliferative response (78%) to HHV-6B was demonstrated in MS patients. Lymphoproliferation to HHV-7 lysate was demonstrated in 23% of healthy controls and 28% of MS patients. These results indicate that the lymphoproliferative response to the HHV-6A variant, which was recently reported to have greater neurotropism, is increased in MS patients.     

Dietary intake of metals and risk of Parkinson's disease: a case-control study in Japan

Although the etiology of multiple sclerosis (MS) is unknown, it is generally believed that genetic, immunologic, and environmental factors are involved. The objectives of this study were: 1. to analyze if a genetic control could explain why HHV-6 would be able to actively replicate in a subset of MS patients but not in controls; 2. to study if MS patients with HHV-6 active replication are clinically different from those without HHV-6 active replication. A total of 195 MS patients and 195 controls were analyzed for two SNPs at the MHC2TA locus and two SNPs at the CD46 locus. Furthermore, the MS cohort was analyzed by PCR for the detection of HHV-6 genomes in five serum samples collected every six months along two-year follow-up. We found that 59/195 (30.2%) MS patients had at least one HHV-6 positive serum sample. No statistical significant difference was found for the two genes when the comparison was made between MS patients and controls; however, a statistical significance was found for the two polymorphisms of MHC2TA when we compared MS patients with active replication and controls (p=0.0000004 for rs4774C and p=0.011 for rs3087456G). Furthermore, increased significant differences were found for MHC2TA and CD46 when we compared interferon beta responders and non-responders within MS patients. In conclusion, we describe a gene-environment interaction in MS patients between HHV-6 and MHC2TA and CD46 that should be further studied to clarify if that interaction could be a genetic control. The results show that MS patients without HHV-6 active replication are better responders to interferon beta treatment than those with HHV-6 active replication.