Special Theme – Association of Herpesviruses with Chronic Disease

Herpesviruses and Multiple Sclerosis
Anthony Simmons, D...
Varicella Zoster Virus                                       patients but not control subjects. The focal point of
vectors responsible for a cluster of MS cases in Key                     Future Investigation
             West (FL, USA)....
               13. Shaw CM, Alvord EC, Jr.                 sclerosis? J Neurovirol 2000;          multiple scle...
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S3624 Herpes Journal 8.3 gk1


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S3624 Herpes Journal 8.3 gk1

  1. 1. Special Theme – Association of Herpesviruses with Chronic Disease Herpesviruses and Multiple Sclerosis Anthony Simmons, Department of Pediatrics and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USA. THE LITERATURE IMPLICATING HERPESVIRUSES IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS (MS) IS REVIEWED, WITH PARTICULAR EMPHASIS ON THE POSSIBLE ASSOCIATION BETWEEN MS AND HUMAN HERPESVIRUS 6 KEY WORDS characteristic changes in the cerebrospinal fluid (CSF). ❚ MULTIPLE SCLEROSIS ❚ PATHOGENESIS No specific treatment was available until recently, when beta interferon and glatiramer acetate were both ❚ AETIOLOGICAL COFACTORS ❚ HERPESVIRUSES ❚ HERPES SIMPLEX shown to reduce the number of potentially damaging VIRUS TYPES 1 AND 2 (HSV-1 AND -2) ❚ VARICELLA ZOSTER VIRUS relapses by approximately one-third. While there have ❚ EPSTEIN-BARR VIRUS (EBV) ❚ CYTOMEGALOVIRUS (CMV) ❚ HUMAN been many suppositions about the mechanisms of HERPESVIRUS 6, 7 AND 8 (HHV-6, -7 AND -8) action of these compounds, the exact reasons for their activity remain unknown. SUMMARY Herpes Simplex Viruses Types 1 and 2 Evidence suggests that multiple sclerosis (MS) is caused by host genetic factors in association with one or more environmental agents. It has been decades since it was first suggested that the The clinical and pathological features of MS implicate viral epidemiology of herpes simplex virus (HSV) infections infections as either cofactors in its aetiology or triggers of relapses, is consistent with their involvement in MS (Table 1).1 although no specific environmental factors have been identified. In For instance, the age at which HSV-2 infections are particular, several herpesviruses have attracted interest because first detected, as well as the age of peak incidence, are their ability to cause latent infections that periodically reactivate has similar to those for MS. If age-specific HSV-1 immunity some familiarity with the relapsing–remitting course of MS. Further, data from various places are compared, an inverse most human herpesviruses can be readily found within the central relationship of immunity levels with latitude is nervous system and several are known to be capable of inducing apparent, and it has been suggested that this might be demyelination, both in humans and in experimentally infected related to the effects of ultraviolet irradiation on HSV-1 animals. This brief review takes a systematic look at reported activation and transmission rates.2 In an attempt to associations between herpesviruses and MS and suggests some unite these observations, it has been suggested that MS criteria that must be met in further studies. One of the greatest is triggered by infection with HSV-2 in persons lacking challenges in confirming or refuting a role for herpesviruses in immunity to HSV-1. Prior HSV-1 immunity, if related chronic diseases is their ubiquitous nature. It is stated from the to subsequent risk of MS, would be protective. This outset that the associations described here remain controversial. hypothesis appears to be consistent with the generalizations concerning effects of migration on subsequent rates of MS, and with certain other features of MS epidemiology.2 Multiple Sclerosis: Background Recent studies showing early neuronal damage in Information MS patients have caused a resurgence of interest in a possible role for the neurotropic alpha-herpesviruses, MULTIPLE SCLEROSIS (MS) PRIMARILY affects young particularly HSV-1 and -2.3 HSV-1 DNA has been adults, particularly women. In its commonest form, MS found in some cases of acute MS but not in stable MS or is characterized clinically by a relapsing and remitting healthy controls. In one study, HSV-1 mRNA and DNA was course with each remission contributing progressive detected in peripheral blood mononuclear cells of a deterioration in clinical condition associated with the significant number of acute MS patients but not in control disease. No symptoms or signs are pathognomonic and subjects. These data indicate that HSV-1 reactivates in diagnosis depends on a combination of characteristic patients during clinical episodes and, therefore, HSV-1 clinical and radiological features together with remains a candidate for a trigger of MS relapses.4 Table 1: Summary of evidence supporting potential roles for herpesviruses in multiple sclerosis Geographical Virus or viral Relapsing– distribution Circumstantial nucleic acid in Plaque-associated Viruses known remitting consistent serological blood or brain viral antigen or to be epidemiology with MS support during acute MS DNA sequences neurotropic HSV1 VZV EBV9,10,13 HSV HHV-623,24 HSV-1 and -2 EBV11 MDV37 HHV-6 HHV-625,26 VZV HHV-620,22 HHV-836–39 MS, multiple sclerosis; HSV, herpes simplex virus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; HHV, human herpesvirus; MDV, Marek’s disease virus. 60 Herpesviruses and MS • HERPES 8:3 2001
  2. 2. Varicella Zoster Virus patients but not control subjects. The focal point of interest, however, is a report by Challoner et al.23 in The association between varicella zoster virus (VZV) which HHV-6 DNA sequences were detected, using and MS is limited largely to clinical experience and representational differential analysis, in the brains of epidemiological surveys. Both MS and varicella are patients with MS. Following this lead, HHV-6 antigen most prevalent in temperate zones and rare in expression was detected in MS brains and shown to be countries close to the equator. Migration studies associated specifically with MS plaques. Subsequently, suggest that exposure to an unidentified environmental plaque-associated DNA sequences have been described agent prior to the age of 14 years is associated with an by others24 and a plethora of reports have surfaced increased risk of MS.5 The prevalence of VZV infection describing looser associations between MS and HHV-6. and MS are both lower in Hutterites, who educate their Some correlate active systemic infection with MS. For children at home, than in their non-Hutterite instance, using a rapid culture assay, Knox et al.25 found neighbours.6 An early serological study found the that blood samples from 22 of 41 patients with definite geometric mean titre of antibodies to VZV to be MS were found to contain active HHV-6 infections, significantly higher among 59 MS cases than among compared with 0 of 61 normal controls (P<0.0001). patients with other diseases and normal individuals.7 While there was no significant difference between In an uncontrolled study, based on improvement of HHV-6 viraemia-positive and HHV-6 viraemia-negative symptoms and pathology after repeated exposure to patients with respect to type of disease (relapsing– high antigen (myelin basic protein) doses in an remitting or progressive), patients with active HHV-6 experimental model of MS, administration of VZV viraemia were significantly younger and experienced a vaccine to MS patients caused apparent benefits, as shorter duration of disease than in HHV-6 viraemia- assessed both clinically and by magnetic resonance negative patients. imaging.8 Berti et al.26 recently confirmed a previous observation that HHV-6 DNA is present in the serum of Epstein-Barr Virus MS patients but not in normal individuals. In addition, it was suggested that HHV-6 viraemia may be A considerable amount of work describing associations correlated with clinical activity. Taus et al.27 analysed a between Epstein-Barr virus (EBV) and MS has been small number of patients for HHV-6 DNA in CSF published over the past 2 decades. All patients with MS samples and peripheral blood mononuclear cells; and have been reported to be EBV seropositive9,10 and antibody titres in serum and CSF. Viral DNA was not cumulative circumstantial evidence points weakly to a detected in CSF or blood and antibody titres were post-pubertal primary EBV infection as a potential comparable between MS and controls. Curiously, this unidentified aetiological event in the induction of MS study reported that 30.4% of MS patients were disease. Perhaps more convincing is an association seronegative to HHV-6, which is far below the normal between EBV reactivation and disease activity in MS prevalence in adults. patients suggesting that EBV might trigger an underlying Human herpesvirus 6 has two variants, A and B, and disease process.11 A cluster of eight cases of MS in the phylogenetic stability of each suggests that they Denmark was correlated significantly with the presence should be regarded as distinct but closely related viruses. of a single subtype of EBV, although the genotyping in There are conflicting reports in the literature regarding this study was limited.12 A report of elevated EBV whether variant A28–30 or B23,31,32 is primarily associated antibody titres during the clinical course of a case of MS with MS, which might be explained in part by the presenting in infancy raises an interesting but still different methodologies used to make the association and speculative aetiological possibility for MS.13 by the divergence of the monoclonal antibody epitope Several groups have reported retrovirus particles or commonly used to identify the viral variants.33 reverse transcriptase activity in lymphocyte cell cultures from MS patients, generally in association with Human Herpesvirus 7 EBV.14–18 Perron et al.19 recently described endogenous retroviral elements integrated into human chromosomal Very little investigation of a possible association regions previously implicated in susceptibility to MS. between human herpesvirus 7 (HHV-7) and MS has been As a consequence, a complex multi-step aetiology of carried out. Four publications make specific reference to MS was proposed, involving triggering of specific HHV-7. The virus has been found to be equally genetic elements by EBV or other infectious agents. prevalent in a latent form in peripheral blood mononuclear cells of MS patients and healthy Cytomegalovirus controls.34 Soldan et al.30 measured the lymphoproliferative response to HHV-7-infected cell There are no reports demonstrating a convincing link lysate and found no significant difference between between MS and cytomegalovirus (CMV). Sanders et patients and controls. In the same study that found no al.20 used a polymerase chain reaction approach to association between MS and HHV-6, Taus et al.27 also compare active with inactive plaques from patients reported no relationship between MS and HHV-7. with MS. CMV sequences were detected in 9–22% of Neither HHV-7 nor HHV-6A antibodies were found in specimens, irrespective of source. Previous research CSF in the previously mentioned study that detected also failed to find significant differences in terms of immunoglobulin M antibodies to HHV-6B.31 CMV seroprevalance between patients with stable MS and control patients.21 Human Herpesvirus 8 Human Herpesvirus 6 As is the case for HHV-6, it has been claimed that human herpesvirus 8 (HHV-8) is strongly neurotropic.35 Human herpesvirus 6 (HHV-6), a recently discovered No evidence has been found to support a specific beta-herpesvirus, is known to cause sporadic cases of association between this virus and MS, however. encephalitis22 and HHV-6 DNA has been found in post-mortem brain samples from MS brains.20 It is, Birds and Marek’s Disease Virus therefore, a neurotropic virus and arguably a commensal of the brain. There are now many reports describing There have been several reports claiming that birds are associations between HHV-6 and MS. Most are based on very likely to be involved as vectors of the exogenous either: detection of HHV-6 antibodies in serum or CSF; causative agent of MS.36–39 In particular, after intensive or amplification of HHV-6 DNA from sera or CSF of MS investigation, wild birds were strongly implicated as Herpesviruses and MS • HERPES 8:3 2001 61
  3. 3. vectors responsible for a cluster of MS cases in Key Future Investigation West (FL, USA). Marek’s disease virus (MDV), a gamma herpesvirus with known neurotropic capacity, emerged Continued research into the pathogenesis of MS is as the most likely pathogen. The discovery that certain assured and an association with viral infections in the EBV and MDV antigens cross react raises the possibility primary pathogenesis or catalysts for demyelinating that prior EBV infection could protect against episodes must always be borne in mind when potentially harmful effects of exposure to MDV, which, formulating hypotheses or interpreting results. For a in part, could explain the complex epidemiology of MS. specific herpesvirus to be considered a candidate, it would obviously be important that all patients have Herpesviruses in the Treatment of MS evidence of past or recent infection, by either serological or lymphoproliferation tests. While an Replication-defective HSV is a candidate for delivery of autoimmune process could be triggered at a site distant exogenous genes into the nervous system. The possibility from MS plaques, direct and ongoing involvement in of using such HSV strains for introducing anti- the process of demyelination means that the virus or inflammatory cytokines (e.g. interleukin 4) into areas of viral antigens should be localized to plaques and viral demyelination has been explored, with some success, in DNA should be detectable in the brain. Positive experimental autoimmune encephalomyelitis (EAE) of findings should be confirmed in a variety of geographic mice.40,41 The concept of introducing genes encoding regions and the initial observation should preferably be neuroprotective agents into the central nervous system is made by a laboratory that has had no prior experience in its infancy and seems guaranteed to receive further with working with the agent involved. To date, only attention. In addition, CMV has been used to deliver one virus, HHV-6, comes close to satisfying these DNA encoding myelin proteolytic protein (PLP) into criteria and antiviral trials will be needed to clarify mice prior to sensitization for EAE, which is a popular any connection. model for studying pathogenetic mechanisms of Perhaps significantly, beta interferon, a demyelination. EAE was exacerbated following neuroprotective drug currently used in the sensitization early after receiving the naked CMV–PLP management of MS, has antiviral activity against DNA construct, whereas late sensitization ameliorated it, HHV-6. Age of infection is known to have a profound a result that has important implications for future influence on the symptoms and tissue tropism attempts to modulate immune responses using this associated with several viral infections. Consequently, approach. Tsunoda et al.42 also reported exacerbation of an issue that merits investigation is the possibility that EAE by a plasmid comprising CMV sequences. late acquisition of one of the ubiquitous pathogens discussed here, presumably between early childhood Is There a Rationale for Antiviral and adolescence, is responsible for triggering the autoimmune process underlying MS. Finally, the Treatment? possibility that MDV or other avian pathogens could be involved should not be regarded as a flight of fancy The results of a randomized, double-blind, placebo- and these potential associations merit further controlled study of aciclovir led Lycke et al.43 to investigation. conclude that aciclovir-susceptible viruses might trigger MS exacerbations. Further studies are justified using valaciclovir with the caveat that several questions need to be resolved before embarking on such a course. First, at what stage of MS is antiviral therapy likely to be most efficacious? Several reports suggest that early treatment might have a better chance Address for correspondence: of a positive result. Secondly, what virus should be Dr Anthony Simmons, Department of Pediatrics and targeted? Clearly, any study should include HHV-6 as a Sealy Center for Vaccine Development, University of major target. Finally, a point that is related to the Texas Medical Branch, Galveston, TX 77555-0739, preceding question, what dosage should be used? USA. Taking into account the wide range of sensitivities to aciclovir of different HHV-6 isolates, the largest dose E-mail: ansimmon@utmb.edu that can be tolerated safely should be used. The current recommendation is that a 2 g dose of oral Received for publication: 1 June 2001 valaciclovir administered every 6 h should be Accepted for publication: 8 August 2001 considered. REFERENCES 1. Vahlne A, Edstrom S, Hanner spectroscopic imaging study. titers by mixed agglutination Wandinger KP. 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Herpesviruses and MS • HERPES 8:3 2001 Herpes in 2002 Two new developments to look out for in Herpes: Independent Submissions • Part-themed rather than fully themed issues; In 2002, we will be actively encouraging independent • Independent submissions. submissions. So, if you have any ideas for articles we will be pleased to hear from you. All unsolicited submissions will Part-themed Issues undergo the same rigorous peer review as commissioned Means we can retain the Journal's reference value on selected articles. topics, while ensuring each issue has something of interest to most readers. It also gives flexibility for late change to the See page 83 for full notes for authors or visit the Journal’s non-themed content. section on the IHMF website at: www.ihmf.org/journal Next year’s themes are planned to include: • Prevention of transmission of genital and neonatal herpes; Tell us your thoughts on these developments or any other • Serological screening for HSV infection; aspect of the Journal by contacting us at: • Transmission of herpesviruses by blood transfusion, Fax: +44 (0) 1903 234862; E-mail: cmp@hbase.com solid-organ transplantation and stem-cell transplantation. 63