Human Herpesvirus 6 - Clinical Significance - Multiple Sclerosis

Multiple Sclerosis

Multiple sclerosis is (MS) an autoimmune and inflammatory disorder of the nervous system that results in demyelination of axons in the brain and spinal cord. The history of MS in the context of HHV-6 began during 1995 when Challoner began looking for non-human genetic sequences in the brains of MS patients. He found an unusually high expression of HHV-6 DNA within oligodendrocytes. He also noticed a higher concentration of infected cells in areas where demyelination had occurred. His research was likely the first published study that suggested a link between HHV-6 and MS.

MS prevalence increases in populations as they are farther from the equator. Incidence is three times higher in those born 42 degrees latitude north and above than in those born 37 degrees north and below. Individuals are also less likely to present with MS as an adult if their childhood was spent in a low incidence region. The possibility of a causative infectious agent in association with MS has been evaluated through the lens of these epidemiological findings.

To explain the data above, two hypotheses were originally proposed. The first is known as the Poliomyelitis hypothesis, and essentially suggests that infection at a young age confers immunity but adult infection increases MS risk. The second is known as the Prevalence hypothesis, and suggests that MS is caused by a pathogen that is more common in regions with high rates of MS. This pathogen would be widespread, and in most individuals would cause an asymptomatic latent infection. Only rarely and years after the primary infection does this agent cause the neurological symptoms of MS. A third hypothesis essentially combines these two and also suggests the involvement of multiple pathogens. The third may best apply to the epidemiological data.

The Epstein-Barr virus (EBV) paradox is also worth mentioning, as HHV-6 has been reported to transactivate EBV. Individuals are at a 10-fold less risk of MS if they are seronegative for EBV. However, among individuals who are positive, those that acquire EBV infection later in life are at a 3-fold greater risk for MS.

Research suggests that viral infections can be tied even closer to MS. EBV antibodies in healthy individuals remain constant, whereas antibody levels in individuals who later develop MS begin to increase and plateau between 20 and 30 years of age, regardless of age of onset.

More specific to HHV-6, researchers in 2004 discovered that the initial stages of MS are associated with high levels of the active virus. Soon thereafter, researchers discovered that levels of active HHV-6 are also elevated during relapses/exacerbations of MS.

Researchers have demonstrated that levels of HHV-6 IgG1 and IgM antibodies are elevated in MS patients relative to controls.

Analysis of the epidemiological, active virus level, and immunological data above supports the plausibility of an infectious agent’s role in MS. However, the exact method of a possible viral influence on the manifestation of MS is less clear. A few of the suggested mechanisms involve molecular mimicry, phosphorylation pathways, and cytokines.

• Multiple sclerosis – molecular mimicry

The first study to specifically investigate HHV-6-related demyelination appeared in the literature during 1996, when a previously healthy 19-month old child developed acute encephalopathy. Levels of myelin basic protein were elevated in his cerebrospinal fluid, suggesting that demyelination was occurring. This link was almost forgotten, until four years later when an MS-related study was published showing an HHV-6 prevalence of 90% among demyelinated brain tissues. In comparison, a mere 13% of disease-free brain tissues possessed the virus.

The molecular mimicry hypothesis, in which T cells are essentially confusing HHV-6 with myelin basic protein, first appeared around this time. Early on in the development of this hypothesis (2002), Italian researchers used the HHV-6a variant along with bovine myelin basic protein to generate cross-reactive T cell lines. These were compared to the T cells of individuals with MS as well as those of controls, and no significant difference was found between the two. Their early research suggested that molecular mimicry may not be a mechanism that is involved in MS.

A few months later, researchers in the United States created a synthetic peptide with a sequence identical to that of an HHV-6 peptide. They were able to show that T cells were activated by this peptide. These activated T cells also recognized and initiated an immune response against a synthetically created peptide sequence that is identical to part of human myelin basic protein. During their research, they found that the levels of these cross-reactive T cells are significantly elevated in MS patients. Their research concluded by suggesting that HHV-6 may indeed be a causative agent for MS.

Several similar studies followed. A variety of methods have been used to assess the cross-reactivation theory and so there are many possible sources for the conflicting results.

• Multiple sclerosis – phosphorylation pathways

Myelin basic protein (MBP) regularly exchanges phosphate groups with the environment, and its ability to do so has implications for proper myelin sheath integrity. More specifically, two threonine residues on MBP have been identified as the phosphorylation targets of glycogen synthase kinase and mitogen-activated protein kinase. Their action on MBP is said to aid in its ability to polymerize and bundle myelin. Phosphorylated MBP is also more resistant to the degradation of several proteases.

Among individuals with MS, these target threonines have been found to be phosphorylated far less often. In fact, HHV-6 produces a transmembrane protein, known as U24, that is also a phosphorylation target of the kinases mentioned above. This is due to a shared sequence of seven amino acids (MBP_92–104 = IVTPRTPPPSQGK; U24_1–13 = MDPPRTPPPSYSE). As a result, essential post-translational modifications may not be occurring for MBPs in individuals with active HHV-6 infections.

• Multiple sclerosis – direct cell damage and altered cytokines

HHV-6 has been shown to infect olfactory ensheathing cells (OECs). OECs have been investigated thoroughly in relation to spinal cord injuries, amyotrophic lateral sclerosis, and other neurodegenerative diseases. Researchers suggest that these cells possess a unique ability to remyelinate injured neurons.

Some of the genes expressed by HHV-6 manipulate host levels of various cytokines (see section on gene products). For instance, infected cells have increased levels of interleukin-8, which is believed to induce MMP-9 elevation. Elevated levels of MMP-9 have been found among individuals with MS.

HHV-6 reactivation has also been implicated in the exacerbation of MS via a shift in Th lymphocyte subsets.