Is There a Role for Human Herpesvirus-6 in the Course of Multiple Sclerosis?

Silvia Delgado, MD, and Micheline McCarthy, MD, PhD

Abstract

Historically, multiple sclerosis (MS) has been associated with many different viruses, including several members of the Herpesviridae family. However, no human or animal virus has been identified as a true “cause” of MS; rather, the epidemiologic and diagnostic data suggest that viral infection may be a cofactor affecting the pathogenesis of MS. Human herpesvirus-6 (HHV-6) is a ubiquitous herpesvirus associated with a common childhood illness, roseola, and this virus is one of those most recently associated with MS. During the past decade, a number of investigations have examined anti–HHV-6-specific antibody responses, HHV-6 viral DNA, or HHV-6 presence in central nervous system (CNS) tissue in both MS patients and controls. There is a growing body of evidence associating HHV-6 infection of the CNS with MS in at least a subpopulation of patients, although the specific factors that define the vulnerable subpopulation(s) of MS patients have not been elucidated. This evidence is provocative but not definitive, and it does not distinguish between HHV-6 as a causal agent in MS versus HHV-6 as a cofactor. Although more clinically based data are needed, the controversy surrounding HHV-6 and MS has again focused attention on the role of viral infection in the clinical and pathologic course of MS.

Suggested citation: Is There a Role for Human Herpesvirus-6 in the Course of Multiple Sclerosis?. Delgado S, McCarthy M. Int J MS Care [Serial on-line]. March 2002;4(1).

Multiple sclerosis (MS) is a chronic, demyelinating disorder in which the immune system attacks the white matter of the central nervous system (CNS). Mechanisms involved in the causes of this disease are complex and multifactorial.¹ Evidence based on animal disease models, such as that derived from Theiler’s murine encephalomyelitis virus infection, supports the theory that infectious agents, including human viruses, may play an important role in the pathogenesis of MS in genetically susceptible individuals.^2-4

Historically, MS has been associated with many different viruses, including several members of the Herpesviridae family.⁵ However, no human or animal virus has been identified as a true “cause” of MS; rather, the epidemiologic and diagnostic data suggest that viral infection may be a cofactor affecting the pathogenesis of MS.⁶ Among human viruses, herpesviruses have certain features that are potentially relevant to the pathogenesis of MS.⁶ Herpesviruses typically cause primary infection in childhood and then follow a lifelong course of latent and recurrent infection, which can persist in the CNS. Several herpesviruses can induce demyelination as well. Human herpesvirus-6 (HHV-6) is a ubiquitous herpesvirus associated with a common childhood illness, roseola (Table 1). This virus is one of those most recently associated with MS.^7,8 The controversy surrounding HHV-6 and MS has again focused attention on the role of viral infection in the clinical and pathologic course of MS.

A viral infection can cause tissue damage within the CNS by different mechanisms. First, a virus may have a direct cytopathic effect on the cell it infects. In this instance, viral replication and the production of progeny virus can destroy the cell’s specialized function(s). An example of this is the CNS demyelination seen in progressive multifocal leukoencephalopathy, a demyelinating disorder in which a polyomavirus (JC) infects astrocytes and oligodendrocytes. Because oligodendrocytes are the principal cells responsible for myelin production in the CNS, their destruction by the JC virus results in loss of myelin. Second, viral infection can act to “trigger” MS attacks by stimulating antiviral immune responses that may not be properly regulated. Increased risk of clinical MS exacerbations following viral infection has been described for upper respiratory tract infections.^9,10 Viruses may act to trigger a local immune response to viral proteins juxtaposed to normal myelin antigens in viral-infected brain or spinal cord, causing secondary inflammation and demyelination.¹¹ Alternatively, viral infection may trigger an autoimmune reaction by “molecular mimicry,” whereby a virus can express antigens with structural homology to normal myelin antigen and thus elicit a mistaken autoimmune attack.¹² In this instance, a viral infection can stimulate antigen-specific clones of T cells, which, after being activated, could enter the CNS and stimulate immune attack on normal “self” antigens expressed within myelinated tissues, again causing damage to myelin. Some authors have suggested that the pathogenesis of demyelination in MS may be heterogeneous within different plaques and among different MS patients.¹³ This concept raises the possibility that different causal agents could be associated with MS lesions, and thus both viral and autoimmune mechanisms could be involved in selected subpopulations of patients.¹⁴

HHV-6: Viral Properties

HHV-6 was first isolated in 1986 from lymphocytes of patients with lymphoproliferative disorders.¹⁵ It is a member of the b-herpesvirus subgroup, closely related to cytomegalovirus (CMV) and human herpesvirus-7 (HHV-7).¹⁶ The viral genome is arranged as a linear segment of double-stranded DNA.¹⁷ HHV-6 can be separated into two strain variants, HHV-6A and HHV-6B, according to DNA restriction analysis, in vitro cellular tropism, and antigenic differences detected by monoclonal antibodies.^18,19 These two HHV-6 variants share a genomic homology of about 94% to 96%.²⁰ Variant HHV-6A is considered more neurotropic than is HHV-6B in that HHV-6A is more frequently identified in cerebrospinal fluid (CSF) than HHV-6B is. However, HHV-6B predominates as the persistent variant in peripheral blood mononuclear cells from both children and adults.²¹ The two variants may have distinct immunologic properties; HHV-6A can infect individuals with prior exposure to HHV-6B. Thus, immunity to HHV-6B does not necessarily prevent infection by HHV-6A.

HHV-6 grows most productively in CD4-expressing T-lymphocytes.²² Efficient HHV-6 replication in primary lymphocyte culture in the laboratory setting requires activation of T-lymphocytes with a mitogen such as phytohemagglutinin and interleukin 2 to stimulate cell proliferation.^15,23,24 HHV-6 also infects other immune system cells such as CD8-expressing T-lymphocytes, natural killer cells, and macrophages.^25,26 The cell surface receptor molecule for HHV-6 has been reported to be CD46.²⁷ CD46 is a glycoprotein present on the surface of all nucleated cells. It protects against spontaneous complement activation on autologous cells. Cermelli and Jacobson recently postulated that virus-induced down-regulation or inactivation of CD46 in genetically predisposed individuals could secondarily allow complement activation, which may lead to myelin damage and increased immune activity against myelin antigens.⁵

HHV-6 infection can induce apoptosis of CD4-expressing T-lymphocytes in vitro and in vivo.^28,29 HHV-6–mediated apoptosis may be caused by cytokines, inflammatory molecules secreted by virus-infected immune cells.³⁰ This could explain the reported susceptibility to apoptosis of uninfected CD4-expressing T-lymphocytes in human HHV-6 infection in vivo.²⁹ The induction of apoptosis in CD4-expressing cells in vivo could cause a dysregulation of the immune system and have important significance in the course of autoimmune disorders such as MS.

HHV-6 also has demonstrated neurotropism, that is, the capacity to grow in the cell types that are found in the brain and spinal cord, including embryonic glia, glioblastoma, and neuroblastoma cell lines, and human fetal astrocytes.25,^31-33 HHV-6 infection in human fetal astrocytes can activate the HIV-1 major gene promoter³⁴; therefore, HHV-6 may act as a cofactor in AIDS-related neurologic disorders and play a similar role in the pathogenesis of MS in association with other viruses. HHV-6 can also infect cultured adult oligodendroglia and microglia,³⁵ which establishes an experimental basis for predicting that HHV-6 can infect oligodendrocytes surrounding MS plaques. HHV-6 has also been reported to infect human endothelial cells in vitro.³⁶ Infection of cerebral vascular endothelial cells could give rise to a chronic inflammation of blood vessels (vasculitis) induced by HHV-6, which may be a mechanism of CNS complications of HHV-6 infection.³⁷ HHV-6 vasculitis would lead to breakdown of the blood-brain barrier and to increased passage of potentially autoreactive immune system cells into the CNS. Therefore, antigens expressed within myelin would be more accessible to immunologic attack.

HHV-6: Infection of the CNS

Epidemiologic studies indicate that more than 90% of all individuals are exposed to HHV-6 during early childhood, probably before age 2.^38,39 The presence of HHV-6 DNA in the CSF has been reported in children with repeated febrile seizures after primary infection⁴⁰ and in the CSF of seven of 10 children with exanthem subitum.⁴¹ HHV-6 DNA has been detected by polymerase chain reaction (PCR) technique in 43% to 85% of specimens of normal human brain tissue.^42-44 Studies have shown an association of HHV-6 with meningitis or encephalitis^45,46 and with increased intrathecal production of anti–HHV-6 early antigen immunoglobulin M (IgM), a possible indicator of viral reactivation in patients with meningitis or encephalitis.⁴⁷ Knox and colleagues directly demonstrated by immunohistochemistry the presence of HHV-6–infected astrocytes, oligodendrocytes, and neurons in autopsy brain tissue from an HIV-infected child with fulminant encephalitis.⁴⁸ These findings suggest that HHV-6 can infect the CNS directly and remain in a latent state in normal or immune-suppressed individuals. Thus, the CNS could be a reservoir of latent or chronic HHV-6 infection, and reactivation could occur locally.⁴⁰

There is additional neuropathologic evidence linking HHV-6 infection with demyelination in the CNS. Yanagihara et al described HHV-6–infected neurons and astrocytes in areas of white matter demyelination found in an adult bone marrow transplant patient with encephalitis.⁴⁹ HHV-6 viral particles were demonstrated within oligodendrocytes in multifocal demyelinating white matter lesions of a patient with fulminant encephalomyelitis.⁵⁰ HHV-6–infected cells have been found in association with areas of active demyelination in postmortem tissues from a patient with subacute demyelinating leukoencephalitis who was previously diagnosed as having MS.⁵¹ In a case report, HHV-6 antigens were demonstrated in astrocytes from a patient with chronic myelopathy and progressive spastic paraparesis associated with demyelination, axonal loss, chronic inflammation, and gliosis.⁵²

HHV-6 and MS: Are They Linked?

Several considerations make HHV-6 a strong candidate to play a role in the course of MS, either as a causal agent or as a cofactor. HHV-6 is a ubiquitous, as well as lymphotropic and neurotropic, virus. It can cause common primary infection in early childhood, and it may remain latent in CNS tissue until optimal conditions permit its reactivation and replication. HHV-6 may induce secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-a), which could promote immune-mediated demyelination in MS.^53,54 As previously described, there is also neuropathologic evidence of an association of HHV-6 with active demyelinating lesions within the CNS.

During the past decade, a number of studies have suggested an association between HHV-6 and MS. These investigations have examined anti–HHV-6-specific antibody responses, HHV-6 viral DNA, or HHV-6 presence in CNS tissue. In 1993, Sola et al reported significantly higher titers of serum anti–HHV-6 antibodies in MS patients compared to normal controls.⁵⁵ In 1997, Soldan et al documented increased serum IgM response to HHV-6 early antigen (p41/38) in relapsing-remitting MS patients compared with chronic progressive MS patients or patients with other neurologic or autoimmune diseases or normal controls.⁵⁶ These researchers also detected HHV-6 DNA in the serum of 15 out of 50 MS patients but in none of 47 non-MS cases studied by PCR. Ablashi et al also found increased serum IgM and IgG responses to HHV-6 early antigen p41/38 in MS patients compared with patients with other neurologic diseases and normal controls.⁵⁷ However, in more recent studies, comparison of serum HHV-6 antibody between MS patients and normal controls showed no differences.⁵⁸

Studies examining HHV-6 DNA have yielded conflicting results. HHV-6 DNA has been detected in the CSF of MS patients but in none of the controls in two reports.^57,59 Other studies have failed to find significant differences in HHV-6 DNA between MS and control groups⁶⁰ or failed to detect serum or CSF HHV-6 DNA in MS patients.^61,62 Fillet et al examined a group of newly diagnosed MS patients (before treatment), but they did not find differences in either the serum or CSF HHV-6 DNA between these MS patients and patients with other neurologic diseases or normal individuals.⁶³ In a recent analysis of HHV-6 viral DNA transcription, Rotola et al concluded that HHV-6 and HHV-7 gene sequences are similarly prevalent in peripheral blood mononuclear cells of MS patients and controls.⁶⁴ However, these viral gene sequences were maintained in a “non-transcriptional state,” typical of latency.

Using immunohistochemical techniques, Challoner et al found expression of HHV-6 antigens in the nuclei of oligodendrocytes associated with demyelinated plaques in brain sections from MS patients but not from controls.⁴³ Knox et al also described HHV-6–infected cells in 90% of CNS tissue sections showing active demyelination, ie, sections associated with inflammatory cells that were obtained from patients with definite MS.⁶⁵ This compared with 13% of tissue sections without active disease, suggesting that HHV-6 infection is prevalent in areas of active demyelination. Using PCR to study postmortem brain samples of MS patients, Sanders et al reported a higher frequency of gene sequences from multiple herpesviruses, including HHV-6, herpes simplex virus (HSV), and varicella zoster virus (VZV), in active demyelinated plaques compared with inactive plaques.⁴⁴ However, the researchers did not find statistically significant differences between MS cases and controls. Thus HHV-6 can associate with other viruses, such as HSV and VZV, that can cause persistent or latent infection of nervous tissues and reactivate in demyelinating plaques. This association may have significance for the pathologic course of MS. HHV-6 could function as a cofactor to facilitate concurrent chronic replication of these other viruses within neural cells. Thus, HHV-6 would indirectly support or promote viral-induced mechanisms of neurologic damage.

Conflicting results among these studies of HHV-6 in MS patients may be due to multiple causes, such as variation in technical protocols, detection of different variants of HHV-6 with different antigenic reactivity, and differences among MS subpopulations studied.⁵ Active HHV-6 viral infection in some MS patients may fluctuate over time during disease progression,⁵⁶ causing inconsistency in viral detection. One recent study found an increased prevalence of HHV-6A in patients with MS,⁶⁶ and earlier studies reported an increased association of MS with HHV-6B.^43,57,67 It remains to be determined if both HHV-6 strain variants could be involved in the development and course of MS in different subpopulations of patients, which possibly could be distinguished by clinical, immune, or genetic parameters. Given the marked heterogeneity of MS lesions and possible involvement of different pathogenic mechanisms (recently reviewed by Noseworthy et al⁶⁸), HHV-6 could be a more or less significant factor in specific, genetically susceptible subpopulations of patients.

It is not possible at this time to conclude that HHV-6 “causes” MS. There is a growing body of evidence associating HHV-6 infection of the CNS with MS in at least a subpopulation of patients, although the specific factors that define the vulnerable subpopulation(s) of MS patients have not been elucidated. This evidence is provocative but not definitive, and it does not distinguish between HHV-6 as a causal agent in MS versus HHV-6 as a cofactor. The pathogenesis and course of HHV-6 infection have interesting parallels to that of MS, and the viral cycles of latency and reactivation could contribute to clinical remissions and exacerbations in susceptible MS patients. Whether HHV-6 is the causal agent of the initial MS “attack,” a local inflammatory reaction in the CNS could stimulate HHV-6 replication in oligodendrocytes by recruiting immunologically activated, CD4-expressing T-lymphocytes that secrete inflammatory molecules. Viral replication in these oligodendrocytes and T-lymphocytes could cause further inflammation and both immune and viral-associated demyelination. This could translate clinically into more severe relapses and higher risk for progressive or permanent disability.

Given the provocative but inconclusive evidence for the role of HHV-6 in the course of MS, more clinically based data are needed. Do HHV-6 latency and reactivation parallel clinical remissions and exacerbations in HHV-6–infected MS patients? Should MS patients at risk for HHV-6 reactivation receive anti-viral medication during MS exacerbations or even during remissions? A useful approach to these questions would be a longitudinal clinical and virologic study of HHV-6 gene expression and specific antibody responses in MS patients to determine whether these markers of HHV-6 infection correlate over time with MS-related clinical and MRI imaging findings. Subpopulations of MS patients with evidence of HHV-6 infection could then participate in clinical trials of effective anti–HHV-6 drugs. A placebo-controlled, double-blind trial of the anti-herpesvirus agent acyclovir in 60 MS patients has already been reported.⁶⁹ Acyclovir tended to reduce the frequency of MS exacerbations and significantly reduced titers of anti-HSV IgG antibodies in treated patients. However, acyclovir is not the optimal anti-viral agent to use against HHV-6. It is commonly used to treat HSV and VZV infections associated with fever blisters or shingles. Ganciclovir and foscarnet, used in the treatment of CMV infection, are more potent anti-viral drugs against beta-herpesviruses such as CMV and HHV-6.6 In addition to specific anti-herpesvirus drugs, the beta-interferons are known to have broad anti-viral effects,⁶ so these MS medications may have some adjunctive effects on HHV-6 infection. There may also be synergy or cooperativity between interferons and specific anti-herpesvirus drugs,⁶ and this possibility could be studied specifically with respect to HHV-6 in MS patients taking interferons. Ultimately, well-controlled clinical trials regarding this issue are the best means to establish whether MS patients could benefit from anti-viral medications and to establish effective doses of these agents and proper protocols for using them as either therapeutic or prophylactic agents.

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