HHV-6, a recently discovered DNA virus, causes exanthem subitum (roseola) in children. Two variants of HHV-6, A and B have been described. HHV-6B causes most human infections whereas no specific human disorder has been linked to HHV-6A. HHV-6 typically causes rash and fever in children but, in addition, this virus commonly enters the CNS during acute primary infections, occasionally resulting in meningitis or other neurological complications (4,113-115). HHV-6 has also been reported to cause encephalitis in immunosuppressed adults and has been linked in a few instances to encephalopathic and myelopathic disorders as well as to human demyelinating disease (116-122).

Almost all children are infected early in life by this ubiquitous virus, with HHV-6 seropositivity being seen in 90% of all children by two years of age (113-115). Like other herpes family viruses, HHV-6 persists lifelong in brain and other tissues in most normal individuals, and—as with other herpes viruses—HHV-6 may be reactivated nonspecifically.

Interest in HHV-6 as a candidate agent in MS intensified following the report by Challoner et al. (4) in 1995, demonstrating HHV-6 variant B group 2 in the brains of greater than 70% of patients with this disease. Although HHV-6 was found in a similar percentage of control brains, viral proteins were identified by immunocyto-chemistry in oligodendrocytes from 12 of 15 MS brain samples but in none of 45 control brains (4). These proteins were preferentially expressed in MS plaques rather than in histologically uninvolved white matter. Similar immunocytochemical findings were found by Knox et al. (123) who reported that 17 of 19 tissue sections that were undergoing active demyelination, obtained from six MS patients, contained HHV-6 proteins, versus none of 15 brain samples from patients with other inflammatory demyelinating diseases. In addition, Knox et al. found HHV-6 antigens in six of nine MS lymph nodes but not in lymphoid tissue from seven controls.

In contrast, other investigators have not identified HHV-6 in any tissue from MS patients (124-126) while some investigators, although finding HHV-6 genome or antigen in MS brain, have noted the lack of specificity for either MS CNS, brain cell types, or to areas of demyelination (127,128). Because herpes viruses can be activated nonspecifically by trauma or alteration in immune status, it is conceivable that the intense inflammatory response, along with the cell death and proliferation that occurs in MS lesions (129), reactivates latent HHV-6. Similarly, HHV-6 could be nonspecifically reactivated in patients previously immunosuppressed with steroids or other drugs. This might explain why brain material from patients with SSPE, progressive multifocal leukoencephalopathy, and HIV can show similar HHV-6 brain findings as in MS (127,128).

HHV-6 variant A and B DNA have also been identified in blood or CSF from some MS patients (123,130-141), but again others have not confirmed these findings or find them to be nonspecific (113,130,133-135).

As to serological responses, reports of higher IgG or IgM antibody titers to HHV-6 or HHV-6B in serum or CSF of MS patients versus controls have been found in several (113,114,131,132,136) but not all studies (137-140) and elevated titers may also be found to other viruses and in other disorders. Similarly, the lymphoproliferative response to HHV-6 antigens as compared to controls has been conflicting (141,142).

Some have reported a relationship between MS disease stage or activity and the presence of HHV-6 DNA, mRNA in blood, or serum IgM antibodies to HHV-6. For example, Villoslada et al. found increased anti HHV-6 IgM serum antibodies in patients in the early phases of MS including patients with a clinically isolated syndrome as compared to patients with secondary progressive MS. This response was not specific since in the same patients IgG antibodies were elevated to EBV and two patients with other neurological diseases also had elevated IgM antibodies to HHV-6 (144). In another study, serum HHV-6 DNA was found in significantly more patients experiencing a clinical exacerbation of MS (4 of 18 samples) as compared to patients deemed to be in clinical remission (11 of 197 samples; P = 0.008) (143). In the most recent study by Alvarez-Lafuente et al. (144) evidence of an active HHV-infection as indicated by HHV-6 DNA in serum and HHV-6 RNA in blood was detected in 16% of patients with RRMS but in no healthy controls (P = 0.003). Among those RRMS patients with active viral replication, viral load was higher during an acute attack than in remission

(P = 0.04). Interestingly, only the HHV-6 A variant was detected, suggesting this variant might be more specifically related to MS.

Although it is difficult to reconcile the pattern of early HHV-6 infection with the worldwide pattern of MS, twin studies, and migration effects, the ultimate test of the HHV-6 hypothesis awaits additional studies and attempts at modifying disease course with antiviral drugs. With regard to the latter, no significant clinical benefit of acyclovir given in a dose of 2.4 g daily was seen (145). Because of concerns about adequacy of dosage and spectrum of the antiviral effect of acyclovir, another study was carried out with valacyclovir, a prodrug of acyclovir that increases acyclovir bioavailability severalfold (146). Again, no significant difference in MRI activity or clinical relapses was found in this double-blind placebo-controlled randomized trial. These therapeutic trials do not exclude the possibility that HHV-6 contributes to MS lesion pathogenesis because sensitivity of the virus to the drug or drug bioa-vailability may be insufficient to benefit MS in the short term. However, weighing all the evidence to date, it seems more likely that HHV-6 is a passenger rather than the driver in MS causation.

Chlamydia pneumoniae

C. pneumoniae, an obligate intracellular bacterium closely related to other chlamydial species including Chlamydia psittaci, Chlamydia trachomatis, and Chlamydia pecorum, was first described in 1986 by Grayston et al. (147). Seroepidemiological studies indicate that about 80% of the population has been exposed to this organism, usually in childhood and young adult life (148,149).

Chlamydial infections are typically mild or asymptomatic but because they may go unrecognized they can cause a chronic low-grade infection. C. pneumoniae is thought to be responsible for approximately 10% of community-acquired pneumonias; other acute symptoms such as headache, abdominal complaints, pharyngitis, and bronchitis are common (148-150). Chlamydia species may also cause neurological disease. For example, C. pecorum has been implicated as a possible causative agent in sporadic bovine encephalomyelitis, and a variety of neurological disorders including meningoencephalitis and GBS have been described with other chlamydial species, including C. pneumoniae. Natural infection with Chlamydia does not necessarily confer lasting immunity, so that reinfections can and do occur. In addition, following immunization against C. trachomatis, reinfections can be clinically more severe than in a primary infection (148).

Several lines of evidence suggest that C. pneumoniae may cause or contribute to atherosclerosis (149,150). For example, seroepidemiological studies suggest that the presence of antibodies to C. pneumoniae doubles one's risk for heart disease. In addition, C. pneumoniae has been found to be present in atherosclerotic lesions by a variety of techniques including PCR, immunocytochemistry, in situ hybridization, enzyme-linked immunosorbent assay (ELISA), and electron microscopy. C. pneumoniae has also been cultured from atherosclerotic arteries. These provocative studies have led to ongoing multicenter trials to determine if treatment with appropriate antibiotics alters the natural history of atherosclerotic complications.

Two chronic neurological disorders have been associated with C. pneumoniae. Balin et al. (151) using PCR identified C. pneumoniae DNA sequences in the brain lesions of 17 of 19 patients with late-onset Alzheimer's disease (AD) but in only 1 of 19 controls. Electron microscopy, immunoelectromicroscopy, reverse transcriptase PCR assays, and immunohistochemical studies also identified C. pneumoniae antigens, transcripts, or C. pneumoniae-like organisms in AD brain specimens, the latter being successfully cultured from AD but not control brains. The demonstration of C. pneumoniae in AD brains by multiple techniques has lent credence to the observation. Unfortunately, at least two other groups using immunocytochemis-try and PCR techniques have failed to confirm the findings of Balin et al. (152,153). While technical differences could explain the difference in results, enthusiasm for an AD-Chlamydia link has waned.

In 1999, Sriram called attention to a possible link between C. pneumoniae and MS (154). In their initial patient with rapidly progressive MS, C. pneumoniae was isolated from the CSF, and treatment with antibiotics resulted in marked neurological improvement. In a follow-up study of 37 patients with MS (17 relapsing-remitting, 20 progressive) and 27 patients with other neurological diseases, C. pneumoniae was isolated from the CSF of 64% of MS patients versus 11% of controls (5). By PCR, C. pneumoniae MOMP gene was identified in the CSF of 97% of MS patients as compared to 18% of controls; by ELISA, 86% of MS patients had C. pneumoniae antibody levels three standard deviations greater than those of controls. The specificity of the antibody response was confirmed by western blot assays following isoelectric focusing of MS CSF. These assays revealed the presence of cationic antibodies in MS CSF reactive against several C. pneumoniae elementary body antigens, particularly to a 75-kDa protein. Sriram also reported that OCBs in MS CSF were partially or completely adsorbed following exposure to C. pneumoniae antigens but not to viral or neural antigens, whereas OCBs in CSF from patients with SSPE were adsorbed by measles but not C. pneumoniae antigens (155). As yet, no reports have confirmed Sriram's observation that MS CSF OCBs, but not control OCBs, react specifically with C. pneumoniae.

In a recent prospective study, Munger et al. (156) measured IgG and IgM antibodies to C. pneumonia in sera collected from patients prior to the clinical development of MS and closely matched controls. The authors concluded that neither C. pneumonia seropositivity nor IgG antibody titers predicted risk of developing MS; however, because of differences in results between cohorts, they could not exclude the possibility that infection with C. pneumonia might modify risk of MS.

If confirmed, these provocative findings would suggest several possible roles for C. pneumoniae in MS. C. pneumonias could cause MS, contribute to lesion pathogen-esis due to entry of infected macrophages and monocytes into the CNS, or be an infectious bystander of no particular relevance to MS lesion genesis or clinical prognosis. Some support for this controversial hypothesis has come from conflicting reports on the detection of C. pneumonia in MS CSF (157) and by the demonstration of increased anti-chlamydia IgG among women with MS as compared to controls (158). Unfortunately, several PCR studies have failed to identify C. pneumoniae in CSF, serum, peripheral blood mononuclear cells, or brain samples obtained from a large number of MS patients (159,160). In one of these studies, no increase in the ratio of CSF to serum antibody titers was found to suggest local production of C. pneumoniae antibody within the CNS (160). The possibility that technical differences between studies might have led to false-negative conclusions cannot be excluded; nevertheless, until further evidence is forthcoming, these findings cast doubt on the Chlamydia MS hypothesis.

Animal Infectious Agents

Several animal viruses cause demyelination in their natural hosts. These include visna, Theiler's virus, murine coronavirus, and CDV. Even if not causative for MS, these animal models may provide valuable insight into mechanisms of virally induced demyelination.

Visna, an RNA lentivirus of sheep, seems unlikely to cause MS, since the worldwide pattern of MS is not compatible with a disease of sheep, and no reports of visna virus genome in MS brain or serological evidence for visna infections of humans have been forthcoming (1). Similarly, antibody titers to the mouse RNA viruses, mouse coronavirus, and Theiler's virus have not been increased in the serum or CSF of MS patients (1), and Theiler's virus genome has not yet been identified in MS brain samples. Although a murine-related coronavirus genome was identified in 12 of 22 MS brain specimens by in situ hybridization, and coronavirus antigen was identified in brain material using immunocytochemical techniques from two patients with rapidly progressive MS (52), others have not been able to confirm the presence of mouse coronavirus genome or to isolate murine coronaviruses from MS tissues (1, Dowling, personal communication). Thus, there is little in the way of hard epidemiological, serological, or microbiological evidence to indicate that these animal viruses are likely to cause MS.

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