HHV-6 and Multiple Sclerosis

ABSTRACT & COMMENTARY

Source: Soldan SS, 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 1997;3:1394-1397.

Soldan and colleagues examined the possible relationship between human herpesvirus 6 (HHV-6) infection and multiple sclerosis. Serum samples from 36 MS patients, 31 with other neurologic disease, 21 with other inflammatory disease, and 14 asymptomatic normal controls, were examined by EIA for IgG and IgM antibody to the p41/38 early antigen of HHV-6.

No significant difference in the anti-HHV-6 IgG response was detected between the groups. However, there was a highly significant difference in the IgM response, particularly between a group of 22 patients with relapsing-remitting MS and normal controls (P < 0.0011). As a further control, IgG and IgM antibodies to EBV and CMV were also examined; there was no significant difference among groups.

A nested PCR was used to detect HHV-6 major capsid protein gene. None was detected in the serum of 18 healthy controls, 19 subjects with other neurologic diseases, or 10 with other inflammatory diseases. In contrast, HHV-6 DNA was detected in 15 (30%) of 50 MS patients (P < 0.0001); 14 of the 15 positives were in subjects with relapsing-remitting MS, and only one patient with chronic progressive MS was positive in this assay.

COMMENT BY STAN DERESINSKI, MD, FACP

HHV-6 is ubiquitous in the human population, with most having been infected in the first two years of life. This high prevalence accounts for the lack of difference between groups in this study in anti-HHV-6 IgG antibody results. Adults do not ordinarily, however, have IgM antibody to this HHV-6, and this virus cannot be detected in their peripheral blood. Thus, the evidence reported here, although only suggestive, strongly raises the possibility of a relationship between chronic HHV-6 infection and MS.

There is increasing evidence that HHV-6 is neurotropic (Infect Dis Alert 1995;15;39-40). "Febrile seizures" are commonly encountered in infants with HHV-6 infection (Hall CB, et al. N Engl J Med 1994;331:432-438). HHV-6 infection has been associated with meningitis in infants, and HHV-6 DNA has been identified in the CSF of a child with exanthem subitum and meningoencephalitis (Yoshikawa T, et al. Pediatrics 1992;89:888-890). This suggests that "febrile seizures" in these patients may, in fact, be a manifestation of meningoencephalitis. HHV-6 DNA can be detected in the CSF of children for a prolonged period of time after acute infection (Caserta MT, et al. J Infect Dis 1994;170:1586-1589). An association of HHV-6 with focal encephalitis resembling HSV encephalitis in adults has been reported (McCullers JA, et al. Clin Infect Dis 1995;21:571-576; reviewed in Infect Dis Alert 1995;15:39-40).

The antigen of HHV-6 used in the EIA by Soldan and colleagues, the p41/38 early antigen, has previously been detected in oligodendroglial cells in MS plaques (Challoner PB, et al. Proc Natl Acad Sci USA 1995;92:7440-7444). This is consistent with a number of observations, including epidemiological, that MS may be caused by an infectious agent. As indicated in an accompanying editorial (Steinman L, Oldstone MBA. Nature Med 1997;3:1321-1322.), a reasonable hypothesis is that the presence of certain viral infections, such as HHV-6, in an individual of appropriate genetic background, particularly with regard to HLA DR, the strongest genetic influence on susceptibility to MS, leads to an ongoing inflammatory response in the central nervous system as the result of molecular mimicry.

Additional candidate viruses are under examination. One intriguing candidate is a novel retrovirus, MSRV (for MS-associated retrovirus), which has been isolated from leptomeningeal, choroid plexus, and from Epstein-Barr virus-immortalized B cells and serum of MS patients (Perron H, et al. Proc Natl Acad Sci USA 1997;94:7583-7588; Garson JA, et al. Lancet 1997; 351:33).

Most people are infected with human herpesvirus 6 (HHV-6) within:

a. the first two years of life.

b. the sixth year of life.

c. the first year of life.

d. the third year of life.

e. the ninth year of life.