Human herpesvirus 6 and multiple sclerosis: the continuing conundrum.

Human herpesvirus 6 (HHV-6) is one of the latest in a long list of infectious agents postulated to play a role in the etiopatho-genesis of multiple sclerosis (MS). It is essential in critically evaluating the still exceedingly controversial association between MS and HHV-6 to understand the basic biology of the virus. HHV-6 was first isolated in 1986 from human peripheral blood mononuclear cells (PBMCs) of patients with lymphoproliferative disorders [1]. Two " variants, " HHV-6A and HHV-6B, that differ enough in their epidemiology , pathogenesis, and genomic sequence to essentially be considered separate viral species have been identified, although not yet taxonomically recognized as such. In 1988, HHV-6B was etiologi-cally associated with a human disease, ex-anthema subitum (ES) [2]. HHV-6A is still essentially an orphan virus, although it is likely to induce disease similar to HHV-6B [3]. HHV-6A and HHV-6B, along with HHV-7, are members of the Roseolovirus genus of the b-herpesvirus subfamily. These viruses share the common properties of ubiquitous prevalence in human populations, a propensity to cause illnesses characterized by fever and rash, and the capacity to grow in lymphoid cells. The basic structure of HHV-6 is similar to that of other herpesviruses and includes a double-stranded DNA genome enclosed in an icosahedral protein capsid surrounded by a tegument. This entire structure is in turn contained within a host-cell–derived lipid envelope into which viral proteins are inserted. Infection is initiated when virus binds to CD46 [4], a 57–67-kDa type I transmembrane glyco-protein expressed on the surface of all nu-cleated human cells. CD46 is 1 of at least 6 glycoproteins belonging to the regulator of complement activation (RCA) protein family, several of which can serve as viral receptors. Interestingly, both HHV-6 and measles can use CD46 as a receptor, although they bind to distinct domains [5]. Increased levels of soluble CD46 can be detected in serum and cerebrospinal fluid (CSF) of patients with MS and other in-flammatory diseases, compared with that in control subjects, although the patho-genetic significance of this remains uncertain [6]. The cell attachment protein of HHV-6 has not been definitely identified, although mapping of neutralization epitopes by monoclonal antibodies indicate that multiple envelope glycoproteins, including gp82-gp105 and the gH-gL complex, are likely candidates. Entry occurs through receptor mediated endocytosis after which the virus envelope is removed, and the nucleocapsid is transported to the nucleus. The subsequent stages of viral replication are likely to be substantially similar …