- Email: [email protected]
Human herpesvirus 6 (hhv-6): Could it play a role in the etiopathogenesis of multiple sclerosis (ms)?
CLINICAL
Vol. 19, No. 617, 1999
thymic 1999.
epithelial
cells. J Virol73:2064-2073,
42. Rothe M, Chene L, Nugeyre MT, Braun J, Barre-Sinoussi F, Israel N: Contact with thymic epithelial cells as a prerequisite for cytokineenhanced human imrnunodeficiency virus type 1 replication in thymocytes. J Virol72:5852-5861, 1998. 43. Schnittman SM. Singer KH, Greenhouse JJ et al.: Thymic microenvironment induces HIV expression. Physiologic secretion of IL-6 by thymic epithelial cells up-regulates virus expression in chronically infected cells (published erratum appears in J 1mmuno148:981,1992). J Immunol 147:2553-2558, 1991. 44. Cameron PU, Lowe MG, Sotzik F, Coughlan AF, Crowe SM, Shortman K: The interaction of macrophage and non-macrophage tropic isolates of HIV-l with thymic and tonsillar dendritic cells in vitro. J Exp Med 183:1851-1856, 1996. 45: Autran B, Guiet P, Raphael M et al.: Thymocyte and thymic microenvironment alterations during a systemic HIV infection in a severe combined immunodelicient mouse model. AIDS 10:717-
727, 1996.
47. Lederman MM, Connick E, Landay A et al.: Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 178:70-79, 1998.
L.F. Kastrukoff,
53. Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M, Akbar AN: IL-7-dependent extrathymic expansion of CD45RA+ T-cells enables preservation of a naive repertoire. J Immunol 161:5909-5917, 1998.
49. Haynes BF, Hale LP, Weinhold KJ et al.: Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-l infection. J Clin Invest 103:921, 1999.
54. Abdul-Hai A, Or R, Slavin S et al.: Stimulation of immune reconstitution by interleukin-7 after syngeneic bone marrow transplantation in mice (published erratum appears in Exp Hematol 1996 24:1540). Exp Hemato124: 1416-1422, 1996.
50. Davis CM, McLaughlin TM, Watson TJ et al.: Normalization of the peripheral blood T-cell receptor V beta repertoire after cultured postnatal human thymic transplantation in DiGeorge syndrome. J Clin Immunol 17:167-175, 1997.
55. Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K: Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 88: 1887-1894, 1996.
it Play (MS)?
Role in the
MD’ and E.E. Thomas, MD, PhD2
Demyelinatinn Disease Studv Grow. Division of Neurology, University of British Columbia’ BC children k-Hospital,2 Vancouver;‘lk, Canada”
T
79
52. Dwyer JM, Wood CC, McNamara J, Kinder B: Transplantation of thymic tissue into patients with AIDS. An attempt to reconstitute the immune system. Arch Intern Med 147:513-517, 1987.
48. Kelleher AD, Al-Harthi L, Landay AL: Immunological effects of antiretroviral and immune therapies for HIV. AIDS 11 Suppl A:Sl49-155, 1997.
Could Sclerosis
Newsletter
5 1. Markert ML, Kostyu DD, Ward FE et al.: Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus. J Immunol 158:998-1005, 1997.
46. Rosenzweig M, Clark DP, Gaulton GN: Selective thymocyte depletion in neonatal HIV-l thymic infection. AIDS 7:1601-1605, 1993.
Human Herpesvirus 6 (H-6): Etiopathogenesis of Multiple
IMMUNOLOGY
he etiology of multiple sclerosis (MS), a demyelinating disease involving the humancentral nervous system (CNS), remainsunknown. Available information suggeststhat it is multifactorial and implicates inherited susceptibility, an autoimmune component, and environmental factors which may be infectious in nature.’ Although specific viruses are known to causea number of chronic neurological diseases,*evidence from epidemiology, serology, and virology studieswhich would implicate a role for viruses in the etiopathogenesisof MS is lessexacting. 3-5Additional support for a viral etiology does,however, come from experimental animal models of virus induced CNS demyelination.2,6 These studiesdemonstratethat different families of viruses are capable of inducing demyelination and raisethe possibility that different viruses could play a role in MS rather then a specific “MS virus.” The modelsalso suggest that causation is multifactorial. The induction of CNS
and Department of Pathology and Laboratory Medicine,
demyelination in many of thesemodels requiresthe interaction of a specific virus with a specific immunerepertoiredetermined by the host’sgenetic make-up. The actual mechanismsmediating the interaction can vary from one systemto the next and may include “hit and run” asin the caseof acute disseminatedencephalomyelitis,6 “molecular mimicry” where homologous peptide sequencesof various viruses and CNS antigenssuch as encephalitogenicregions of myelin basic protein may be shared,7-9 and “epitope spreading” where immune responses develop becauseof de novo priming of self-reactive T-cells to sequestered autoantigensreleasedsecondaryto virusspecific T-cell-mediated demyelination.lo While human herpesvirus6 (HHV-6) hasonly recently beenimplicated in the etiopathogenesisof MS, the idea that membersof the herpesviridaefamily of virusesmay play a role in this diseaseis not new. Herpessimplex virus (HSV) was isolated from the brain of a MS patient by 0 1999 Elsevier
Science Inc.
Gudnadottir et al.” in 1964and from the cerebrospinalfluid (CSF) of a secondMS patient by Bergstrom et al.12Furthermore, Fraseret al.,13using Southern blot hybridization, were able to identify HSV DNA in the CNS of a number of MS patients. The interpretation of theseresults was made difficult however by the fact that HSV DNA wasalso found in the CNS of controls without MS.‘3-‘7 Recently, Sanders et al.‘8,19have extended thesestudiesby using polymerase chain reaction (PCR) and Southern blot hybridization techniques.They also found HSV DNA to be presentin the CNS of both MS patients and controls but found viral DNA to be more likely associatedwith active rather then inactive plaques.Although these associationsare very intriguing, they are not proof that HSV is responsible for the induction of CNS demyelination in MS patients. Even if it were to be shown that HSV is capableof inducing CNS demyelination, the presenceof viral DNA in the CNS of both MS patients and con-
0197-1859/99
(see frontmatter)
80 CLINICAL
IMMUNOLOGY
Newsletter
trols would suggest that other factors besides virus are required. In an experimental animal model, HSV 1 has been shown to induce recurrent multifocal CNS demyelination but only in specific strains of mice and with specific strains of virus.20-22 In some murine strains, HSV 1 can be found throughout the CNS following oral inoculation with virus but without the development of demyelinating lesions.21 Other members of the Herpesviridae family of viruses have also been implicated in the etiopathogenesis of MS. Evidence implicating Epstein-Barr virus (EBV) in MS has recently been reviewed by Munch et al.23while Ross et al.” makes a case for an association between varicellazoster virus (VZV) and MS using an epidemiologic approach. Using PCR, Sanders et al. were able to find viral DNA from EBV and cytomegalovirus (CMV) in the CNS of both MS patients and controls but at a lower incidence then HSV, HHV-6 or VZV.” It is not known if different members of the Herpesviridae family of viruses may contain conserved genetic sequences which are important to the induction of CNS demyelination in susceptible hosts. HHV-6, a beta-herpesvirus, was first isolated in Robert Gallo’s laboratory at the National Cancer Institute in 1986.25 It was initially identified in the peripheral blood of immunosuppressed patients affected by various lymphoproliferative diseases. The molecular and structural characteristics of HHV-6 have been extensively reviewed by LUSSO~~and Braun et al. 27There are two m aj or subgroups or variants of HHV-6 (A and B) which have been defined on the basis of DNA restriction analysis, in vitro tropism, and antigenic relationships defined by monoclonal antibodies.28 Furthermore, multiple strains of the variants exist. Examples of these include strains GS and U 1102 of the A variant and strains 229 and HST of the B variant.29 Strains of variant B can be further designated as belonging to one of two groups: group 1 or group 2. Although thevariants differ genetically, immunologically, and biologically, they do share a tropism for T-lymphocytes (primarily CD4 T-cells), macrophages,30 and NK cells. Infection by HHV-6 is the most ubiquitous of all human herpesviruses3’ and is present throughout different geographic areas.32
The virus is likely acquired through transmission of oropharyngeal secretions26 and within the first one to three years of life.33 HHV-6 is detectable post-mortem in the CNS of many neurologically normal adults34 and it has been suggested that the CNS may be the sole site of persistence of this vit-u~.~~ Clinically, HHV-6 causes exanthem subitum (roseola infanturn) in children.36 Only HHV-6B strains definitively have been proven to cause disease. Although infection with this virus is often mild, it can cause a spectrum of illness including neurological disease.37 Seizures are a frequent complication of primary HHV-6 infection in infants while encephalitis and meningoencephalitis are more rare.38 In those cases of virus-associated CNS disease, HHV-6 DNA can frequently be detected in the CSF.38-40HHV-6 CNS infections also have been reported in immunosuppressed patients such as bone marrow transplant patients41 and adults/ children with AIDS.42A3 It is of interest that in several of these cases, the neuropathology involved either extensive demyelination of the subcortical white matter or focal areas of demyelination.40”‘*a Recently, HHV-6 has been implicated in the etiopathogenesis of MS. Evidence to support this comes from several avenues of investigation including anecdotal reports, serological studies in serum and CSF, detection of viral nucleic acid in serum and CSF, and detection of HHV-6 in the CNS. Among the anecdotal reports, Merelli et a1.45reported the development of an acute encephalopathy in a MS patient. The patient was a known carrier of HHV-6 as specific viral genomic sequences were detected in peripheral ’ blood mononuclear cells (PBMC) but not CSF prior to the event. During the acute encephalopathy, CSF was positive for HHV-6 genomic sequences at a time when new lesions were identified on the MRI. Furthermore, Carrigan et a1.46 reported the case of a young woman who died of a subacute demyelinating disease which clinically and pathologically were diagnosed as MS. Using an immunohistochemical approach, the authors were able to identify a disseminated active HHV-6 infection which correlated with the areas of demyelination. A similar case was reported by Novoa et a14’ where a young
Vol. 19. No. 6/7, 1999
woman, who developed a fulminant demyelinating encephalomyelitis, had HI-IV-6 associated with the demyelinating lesions as detected by immunohistochemistry and PCR both on brain biopsy and brain tissue at the time of autopsy. Although one could argue that these two cases were “atypical” for MS, it would likely have been the diagnosis were it not for the newer diagnostic techniques. Furthermore, it is reminiscent of those patients who originally were diagnosed as suffering from MS but where later the diagnosis was changed once it was realized that a separate condition, TSP/HAM is caused by HTLV- 1. Several serological studies have looked at differences in antibodies to HHV-6 in MS patients and controls. Sola et a1.,48 using an immunofluorescence analysis of sera, found anti-HHV-6 antibody titers to be significantly higher in 126 MS patients compared with 500 normal controls. However, as PCR of the PBMC was only positive for HHV-6 in one MS and one control, they interpreted their results as being more consistent with immune impairment observed among MS patients rather then resulting from reactivation of a latent infection. In a similar type of study, Wilborn et a1.49studied 21 MS patients and compared the results with 19 patients with facial palsy, seven with Guillain-Barre syndrome, and 16 controls. Using an ELISA analysis of sera they also found anti-HHV-6 antibody titers to be significantly higher than in control groups. PCR of the PBMC was negative for HHV-6 in both the MS and controls. In contrast, Nielsen et a1.50studied 189 serum samples from MS patients at differ,ent stages of their disease and compared them with 190 serum samples from age and sex matched controls. Only two of the controls and none of the MS patients were sero-negative for antibodies to HHV-6. No significant difference was found in the anti-HHV-6 IgG titers between MS patients and controls using a competitive ELISA technique. In this study, PCR of the PBMC was not performed for HHV-6. When taken together the results support the ubiquitous nature of infection with HHV-6 as most individuals were sero-positive for this virus. It is less clear if higher titers of antibody to HHV-6 are a consistent finding among
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MS patients. Recently, Soldan et al. (51) using an EIA, examined serum for antibodies to HHV-6 p41/38 early antigen from 36 (22 relapsing-remitting [R/R], 14 chronic progressive[CP]) MS patients, 3 1 other neurological diseases (OND), 2 1 other inflammatory diseases (OID), and 14 normal controls. Although there was no difference in the anti-HHV-6 IgG response to HHV-6 p41/38 early antigen, there was a significantly elevated IgM response in the R/R group. Similar differences in IgG or IgM antibodies to EBV or CMV were not identified. In one cohort of this study, IgM antibodies to p41/38 HHV-6 early antigen in the CSF were not found among 18 RRMS, 6 CPMS, or 18 HAM/TSP patients. HHV-6 DNA was not identified, using PCR, in the PBMC of 47 normal controls or patients with OND or OID. It was found however in 15 (14 RRMS, 1 CPMS) of 50 MS patients. The authors suggested that the results represented a reactivation of latent HHV-6 in MS patients but they were not prepared to conclude that HHV-6 is the causative agent of MS. The third avenue of investigation involves the identification of HHV-6 nucleic acid in the blood or CSF of MS patients. Martin et al. (52) were not able to identify HHV-6 DNA in blood using PCR in over 116 samples obtained from MS, optic neuritis and OND. Similar results were obtained by Wilborn et al.49 In contrast, Sola et a1.48were able to identify viral DNA in the blood but in only 1 of 31 MS patients and 1 of 24 normal controls while Merelli et als3 reported the presence of HHV-6 nucleic acid in PBMC of 3 of 56 MS patients. Soldan et a1.51 reported a higher rate with 30% of 50 MS patients having viral DNA in their blood but none of 47 controls. Recently, Mayne et a1.54used two separate probes to target different regions within the HHV-6 genome. Depending on which probe was employed, detection of HHV-6 genome ranged from 11.7 to 23.5% in controls, 3.1 to 23% in RRMS, and 14.2 to 28.5% in CPMS. Martin et a1.52did not find HHV-6 DNA in any of 115 CSF samples obtained from patients with MS, optic neuritis, or OND. In contrast, Wilborn et a1.49did find viral DNA in 3 of 21 MS patients but not in their controls. Similar results were reported by Liedtke et a1.55In
acellular CSF, HHV-6 was detected in 4 of 36 MS patients, 2 of 27 neuro-AIDS patients, but in none of their control group. The fourth avenue of investigation involves the detection of viral DNA in the CNS and their relation to MS lesions. Challoner et al.56used representational difference analysis to search for pathogens in MS brains. Using PCR in 86 brain specimens, HHV-6 DNA was identified in >70% of MS cases and controls. These results along with studies by Luppi et a1.34 and Saunders et a1.19indicate that HHV-6 is a commensal virus of the human brain. Not all investigators however have found HI-IV-6 DNA in the CNS of MS patients.53 Using DNA sequencing, Challoner et al. found most of the HHV-6 were variant B group 2 in nature but one isolate was found to be variant B group 1. In most of the 49 MS patients, viral titers were similar to that found in controls. However, in two MS patients, markedly higher titers were found. Further study of the viral isolates from these two MS patients found Hind HI restriction site polymorphisms which suggested that there may be subtypes of HHV-6 variant B group 2 which differ in their biological behavior. Immunocytochemistry studies employing antibodies to HHV-6 virion protein 101 K and DNA binding protein p41 were of particular interest. Nuclear staining of oligodendrocytes by these antibodies was found in 12 of 15 MS patients but not in controls suggesting a fundamental difference between the two groups. Further support for this observation comes from in vitro studies where HHV-6 was found to have a tropism for oligodendrocytes and microglia but not neurons.57 Although evidence is mounting for a possible role of HHV-6, along with other ’ members of the Herpesviridae family of viruses, in the etiopathogenesis of multiple sclerosis, it is important to realize that association does not prove causation. Historically, the search for infectious agents which may play an etiologic role in MS has been a difficult one and of necessity must raise a healthy skepticism whenever new viral agents are claimed to play a role. Nevertheless, the potential of Herpesviruses, and HHV-6 in particular, to play a role represents an exciting development in MS research and one which hopefully will become clear in the near future. 8 1999 Elsevier Science Inc.
Author’s
ZVewsZeffer81
e-mail Address
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Newsletter
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0 1999 Elsevier Science Inc.
46. Canigan DR, Harrington D, Knox KK: Subacute leukoencephalitis caused by CNS infection with human herpesvirus- manifesting as acute multiple sclerosis. Neurology 47:145-148, 1996. 47. Novoa LJ, Nagra RM, Nakawatase T et al.: Fulminant demyelinating encephalo-myelitis associated with productive HHV-6 infection in an immunocompetent adult. J Med Vii01 52:301-308, 1997. 48. Sola P, Merelli E, Marasca R et al.: Human herpesvirus 6 and multiple sclerosis: survey of anti-HHV-6 antibodies by immunofluorescence analysis and of viral sequencesby polymerase chain reaction. J Neurol Neurosurg Psych 56:917-919, 1993. 49. Wilbom F, Schmidt CA, Brinkmann V et al.: A potential role for human herpesvirus type 6 in nervous systemdisease. J Neuroimmunol 49:213-214, 1994. 50. Nielsen L, Moller-Larsen A, Munk A et al.: Human herpesvirus- immunoglobulin G antibodies in patients with multiple sclerosis. Acta Neurol Scan (suppl) 169:76-78, 1997. 51. Soldan SS, Berti R, Salem N et al.: Association of human herpes virus 6 (HHV-6) with multiple sclerosis: Increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nature Med 3:1394-1397.1997. 52. Martin C, Enbom M, Soderstrom M et al.: Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis. Acta Neural Stand 95:280-283, 1997. 53. Merelli E, Bedin R, Sola Pet al.: Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children. J Neurol 244:450-454, 1997. 54. Mayne M, Krishnan J, Metz Let al.: Infrequent detection of human herpesvirus 6 DNA in peripheral blood mononuclear cells from multiple sclerosis patients. Ann Nemo1 44391-394, 1998. 55. Liedtke W, Malessa R, Faustmann PM et al.: Human herpesvirus 6 polymerase chain reaction findings in human immunodeficiency virus associated neurological disease and multiple sclerosis. J Neurovirol 1:253-358, 1995. 56. Challoner PB, Smith KT, Parker JD et al.: Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. PNAS (USA) 92:7440-7444, 1995. 57. Albright AV, Lavi E, Black JB et al.: The effect of human herpesvirus- (HHV-6) on cultured human neural cells: oligodendrocytes and microglia. J Neurovirol4:486-494, 1998.
Vol. 19, No. 617, 1999
thymic 1999.
epithelial
cells. J Virol73:2064-2073,
42. Rothe M, Chene L, Nugeyre MT, Braun J, Barre-Sinoussi F, Israel N: Contact with thymic epithelial cells as a prerequisite for cytokineenhanced human imrnunodeficiency virus type 1 replication in thymocytes. J Virol72:5852-5861, 1998. 43. Schnittman SM. Singer KH, Greenhouse JJ et al.: Thymic microenvironment induces HIV expression. Physiologic secretion of IL-6 by thymic epithelial cells up-regulates virus expression in chronically infected cells (published erratum appears in J 1mmuno148:981,1992). J Immunol 147:2553-2558, 1991. 44. Cameron PU, Lowe MG, Sotzik F, Coughlan AF, Crowe SM, Shortman K: The interaction of macrophage and non-macrophage tropic isolates of HIV-l with thymic and tonsillar dendritic cells in vitro. J Exp Med 183:1851-1856, 1996. 45: Autran B, Guiet P, Raphael M et al.: Thymocyte and thymic microenvironment alterations during a systemic HIV infection in a severe combined immunodelicient mouse model. AIDS 10:717-
727, 1996.
47. Lederman MM, Connick E, Landay A et al.: Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 178:70-79, 1998.
L.F. Kastrukoff,
53. Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M, Akbar AN: IL-7-dependent extrathymic expansion of CD45RA+ T-cells enables preservation of a naive repertoire. J Immunol 161:5909-5917, 1998.
49. Haynes BF, Hale LP, Weinhold KJ et al.: Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-l infection. J Clin Invest 103:921, 1999.
54. Abdul-Hai A, Or R, Slavin S et al.: Stimulation of immune reconstitution by interleukin-7 after syngeneic bone marrow transplantation in mice (published erratum appears in Exp Hematol 1996 24:1540). Exp Hemato124: 1416-1422, 1996.
50. Davis CM, McLaughlin TM, Watson TJ et al.: Normalization of the peripheral blood T-cell receptor V beta repertoire after cultured postnatal human thymic transplantation in DiGeorge syndrome. J Clin Immunol 17:167-175, 1997.
55. Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K: Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 88: 1887-1894, 1996.
it Play (MS)?
Role in the
MD’ and E.E. Thomas, MD, PhD2
Demyelinatinn Disease Studv Grow. Division of Neurology, University of British Columbia’ BC children k-Hospital,2 Vancouver;‘lk, Canada”
T
79
52. Dwyer JM, Wood CC, McNamara J, Kinder B: Transplantation of thymic tissue into patients with AIDS. An attempt to reconstitute the immune system. Arch Intern Med 147:513-517, 1987.
48. Kelleher AD, Al-Harthi L, Landay AL: Immunological effects of antiretroviral and immune therapies for HIV. AIDS 11 Suppl A:Sl49-155, 1997.
Could Sclerosis
Newsletter
5 1. Markert ML, Kostyu DD, Ward FE et al.: Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus. J Immunol 158:998-1005, 1997.
46. Rosenzweig M, Clark DP, Gaulton GN: Selective thymocyte depletion in neonatal HIV-l thymic infection. AIDS 7:1601-1605, 1993.
Human Herpesvirus 6 (H-6): Etiopathogenesis of Multiple
IMMUNOLOGY
he etiology of multiple sclerosis (MS), a demyelinating disease involving the humancentral nervous system (CNS), remainsunknown. Available information suggeststhat it is multifactorial and implicates inherited susceptibility, an autoimmune component, and environmental factors which may be infectious in nature.’ Although specific viruses are known to causea number of chronic neurological diseases,*evidence from epidemiology, serology, and virology studieswhich would implicate a role for viruses in the etiopathogenesisof MS is lessexacting. 3-5Additional support for a viral etiology does,however, come from experimental animal models of virus induced CNS demyelination.2,6 These studiesdemonstratethat different families of viruses are capable of inducing demyelination and raisethe possibility that different viruses could play a role in MS rather then a specific “MS virus.” The modelsalso suggest that causation is multifactorial. The induction of CNS
and Department of Pathology and Laboratory Medicine,
demyelination in many of thesemodels requiresthe interaction of a specific virus with a specific immunerepertoiredetermined by the host’sgenetic make-up. The actual mechanismsmediating the interaction can vary from one systemto the next and may include “hit and run” asin the caseof acute disseminatedencephalomyelitis,6 “molecular mimicry” where homologous peptide sequencesof various viruses and CNS antigenssuch as encephalitogenicregions of myelin basic protein may be shared,7-9 and “epitope spreading” where immune responses develop becauseof de novo priming of self-reactive T-cells to sequestered autoantigensreleasedsecondaryto virusspecific T-cell-mediated demyelination.lo While human herpesvirus6 (HHV-6) hasonly recently beenimplicated in the etiopathogenesisof MS, the idea that membersof the herpesviridaefamily of virusesmay play a role in this diseaseis not new. Herpessimplex virus (HSV) was isolated from the brain of a MS patient by 0 1999 Elsevier
Science Inc.
Gudnadottir et al.” in 1964and from the cerebrospinalfluid (CSF) of a secondMS patient by Bergstrom et al.12Furthermore, Fraseret al.,13using Southern blot hybridization, were able to identify HSV DNA in the CNS of a number of MS patients. The interpretation of theseresults was made difficult however by the fact that HSV DNA wasalso found in the CNS of controls without MS.‘3-‘7 Recently, Sanders et al.‘8,19have extended thesestudiesby using polymerase chain reaction (PCR) and Southern blot hybridization techniques.They also found HSV DNA to be presentin the CNS of both MS patients and controls but found viral DNA to be more likely associatedwith active rather then inactive plaques.Although these associationsare very intriguing, they are not proof that HSV is responsible for the induction of CNS demyelination in MS patients. Even if it were to be shown that HSV is capableof inducing CNS demyelination, the presenceof viral DNA in the CNS of both MS patients and con-
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trols would suggest that other factors besides virus are required. In an experimental animal model, HSV 1 has been shown to induce recurrent multifocal CNS demyelination but only in specific strains of mice and with specific strains of virus.20-22 In some murine strains, HSV 1 can be found throughout the CNS following oral inoculation with virus but without the development of demyelinating lesions.21 Other members of the Herpesviridae family of viruses have also been implicated in the etiopathogenesis of MS. Evidence implicating Epstein-Barr virus (EBV) in MS has recently been reviewed by Munch et al.23while Ross et al.” makes a case for an association between varicellazoster virus (VZV) and MS using an epidemiologic approach. Using PCR, Sanders et al. were able to find viral DNA from EBV and cytomegalovirus (CMV) in the CNS of both MS patients and controls but at a lower incidence then HSV, HHV-6 or VZV.” It is not known if different members of the Herpesviridae family of viruses may contain conserved genetic sequences which are important to the induction of CNS demyelination in susceptible hosts. HHV-6, a beta-herpesvirus, was first isolated in Robert Gallo’s laboratory at the National Cancer Institute in 1986.25 It was initially identified in the peripheral blood of immunosuppressed patients affected by various lymphoproliferative diseases. The molecular and structural characteristics of HHV-6 have been extensively reviewed by LUSSO~~and Braun et al. 27There are two m aj or subgroups or variants of HHV-6 (A and B) which have been defined on the basis of DNA restriction analysis, in vitro tropism, and antigenic relationships defined by monoclonal antibodies.28 Furthermore, multiple strains of the variants exist. Examples of these include strains GS and U 1102 of the A variant and strains 229 and HST of the B variant.29 Strains of variant B can be further designated as belonging to one of two groups: group 1 or group 2. Although thevariants differ genetically, immunologically, and biologically, they do share a tropism for T-lymphocytes (primarily CD4 T-cells), macrophages,30 and NK cells. Infection by HHV-6 is the most ubiquitous of all human herpesviruses3’ and is present throughout different geographic areas.32
The virus is likely acquired through transmission of oropharyngeal secretions26 and within the first one to three years of life.33 HHV-6 is detectable post-mortem in the CNS of many neurologically normal adults34 and it has been suggested that the CNS may be the sole site of persistence of this vit-u~.~~ Clinically, HHV-6 causes exanthem subitum (roseola infanturn) in children.36 Only HHV-6B strains definitively have been proven to cause disease. Although infection with this virus is often mild, it can cause a spectrum of illness including neurological disease.37 Seizures are a frequent complication of primary HHV-6 infection in infants while encephalitis and meningoencephalitis are more rare.38 In those cases of virus-associated CNS disease, HHV-6 DNA can frequently be detected in the CSF.38-40HHV-6 CNS infections also have been reported in immunosuppressed patients such as bone marrow transplant patients41 and adults/ children with AIDS.42A3 It is of interest that in several of these cases, the neuropathology involved either extensive demyelination of the subcortical white matter or focal areas of demyelination.40”‘*a Recently, HHV-6 has been implicated in the etiopathogenesis of MS. Evidence to support this comes from several avenues of investigation including anecdotal reports, serological studies in serum and CSF, detection of viral nucleic acid in serum and CSF, and detection of HHV-6 in the CNS. Among the anecdotal reports, Merelli et a1.45reported the development of an acute encephalopathy in a MS patient. The patient was a known carrier of HHV-6 as specific viral genomic sequences were detected in peripheral ’ blood mononuclear cells (PBMC) but not CSF prior to the event. During the acute encephalopathy, CSF was positive for HHV-6 genomic sequences at a time when new lesions were identified on the MRI. Furthermore, Carrigan et a1.46 reported the case of a young woman who died of a subacute demyelinating disease which clinically and pathologically were diagnosed as MS. Using an immunohistochemical approach, the authors were able to identify a disseminated active HHV-6 infection which correlated with the areas of demyelination. A similar case was reported by Novoa et a14’ where a young
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woman, who developed a fulminant demyelinating encephalomyelitis, had HI-IV-6 associated with the demyelinating lesions as detected by immunohistochemistry and PCR both on brain biopsy and brain tissue at the time of autopsy. Although one could argue that these two cases were “atypical” for MS, it would likely have been the diagnosis were it not for the newer diagnostic techniques. Furthermore, it is reminiscent of those patients who originally were diagnosed as suffering from MS but where later the diagnosis was changed once it was realized that a separate condition, TSP/HAM is caused by HTLV- 1. Several serological studies have looked at differences in antibodies to HHV-6 in MS patients and controls. Sola et a1.,48 using an immunofluorescence analysis of sera, found anti-HHV-6 antibody titers to be significantly higher in 126 MS patients compared with 500 normal controls. However, as PCR of the PBMC was only positive for HHV-6 in one MS and one control, they interpreted their results as being more consistent with immune impairment observed among MS patients rather then resulting from reactivation of a latent infection. In a similar type of study, Wilborn et a1.49studied 21 MS patients and compared the results with 19 patients with facial palsy, seven with Guillain-Barre syndrome, and 16 controls. Using an ELISA analysis of sera they also found anti-HHV-6 antibody titers to be significantly higher than in control groups. PCR of the PBMC was negative for HHV-6 in both the MS and controls. In contrast, Nielsen et a1.50studied 189 serum samples from MS patients at differ,ent stages of their disease and compared them with 190 serum samples from age and sex matched controls. Only two of the controls and none of the MS patients were sero-negative for antibodies to HHV-6. No significant difference was found in the anti-HHV-6 IgG titers between MS patients and controls using a competitive ELISA technique. In this study, PCR of the PBMC was not performed for HHV-6. When taken together the results support the ubiquitous nature of infection with HHV-6 as most individuals were sero-positive for this virus. It is less clear if higher titers of antibody to HHV-6 are a consistent finding among
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MS patients. Recently, Soldan et al. (51) using an EIA, examined serum for antibodies to HHV-6 p41/38 early antigen from 36 (22 relapsing-remitting [R/R], 14 chronic progressive[CP]) MS patients, 3 1 other neurological diseases (OND), 2 1 other inflammatory diseases (OID), and 14 normal controls. Although there was no difference in the anti-HHV-6 IgG response to HHV-6 p41/38 early antigen, there was a significantly elevated IgM response in the R/R group. Similar differences in IgG or IgM antibodies to EBV or CMV were not identified. In one cohort of this study, IgM antibodies to p41/38 HHV-6 early antigen in the CSF were not found among 18 RRMS, 6 CPMS, or 18 HAM/TSP patients. HHV-6 DNA was not identified, using PCR, in the PBMC of 47 normal controls or patients with OND or OID. It was found however in 15 (14 RRMS, 1 CPMS) of 50 MS patients. The authors suggested that the results represented a reactivation of latent HHV-6 in MS patients but they were not prepared to conclude that HHV-6 is the causative agent of MS. The third avenue of investigation involves the identification of HHV-6 nucleic acid in the blood or CSF of MS patients. Martin et al. (52) were not able to identify HHV-6 DNA in blood using PCR in over 116 samples obtained from MS, optic neuritis and OND. Similar results were obtained by Wilborn et al.49 In contrast, Sola et a1.48were able to identify viral DNA in the blood but in only 1 of 31 MS patients and 1 of 24 normal controls while Merelli et als3 reported the presence of HHV-6 nucleic acid in PBMC of 3 of 56 MS patients. Soldan et a1.51 reported a higher rate with 30% of 50 MS patients having viral DNA in their blood but none of 47 controls. Recently, Mayne et a1.54used two separate probes to target different regions within the HHV-6 genome. Depending on which probe was employed, detection of HHV-6 genome ranged from 11.7 to 23.5% in controls, 3.1 to 23% in RRMS, and 14.2 to 28.5% in CPMS. Martin et a1.52did not find HHV-6 DNA in any of 115 CSF samples obtained from patients with MS, optic neuritis, or OND. In contrast, Wilborn et a1.49did find viral DNA in 3 of 21 MS patients but not in their controls. Similar results were reported by Liedtke et a1.55In
acellular CSF, HHV-6 was detected in 4 of 36 MS patients, 2 of 27 neuro-AIDS patients, but in none of their control group. The fourth avenue of investigation involves the detection of viral DNA in the CNS and their relation to MS lesions. Challoner et al.56used representational difference analysis to search for pathogens in MS brains. Using PCR in 86 brain specimens, HHV-6 DNA was identified in >70% of MS cases and controls. These results along with studies by Luppi et a1.34 and Saunders et a1.19indicate that HHV-6 is a commensal virus of the human brain. Not all investigators however have found HI-IV-6 DNA in the CNS of MS patients.53 Using DNA sequencing, Challoner et al. found most of the HHV-6 were variant B group 2 in nature but one isolate was found to be variant B group 1. In most of the 49 MS patients, viral titers were similar to that found in controls. However, in two MS patients, markedly higher titers were found. Further study of the viral isolates from these two MS patients found Hind HI restriction site polymorphisms which suggested that there may be subtypes of HHV-6 variant B group 2 which differ in their biological behavior. Immunocytochemistry studies employing antibodies to HHV-6 virion protein 101 K and DNA binding protein p41 were of particular interest. Nuclear staining of oligodendrocytes by these antibodies was found in 12 of 15 MS patients but not in controls suggesting a fundamental difference between the two groups. Further support for this observation comes from in vitro studies where HHV-6 was found to have a tropism for oligodendrocytes and microglia but not neurons.57 Although evidence is mounting for a possible role of HHV-6, along with other ’ members of the Herpesviridae family of viruses, in the etiopathogenesis of multiple sclerosis, it is important to realize that association does not prove causation. Historically, the search for infectious agents which may play an etiologic role in MS has been a difficult one and of necessity must raise a healthy skepticism whenever new viral agents are claimed to play a role. Nevertheless, the potential of Herpesviruses, and HHV-6 in particular, to play a role represents an exciting development in MS research and one which hopefully will become clear in the near future. 8 1999 Elsevier Science Inc.
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