The Multiple Sclerosis-Associated RetroVirus (MSRV) isolated from Plasma of MS patients was found to be phylogenetically and experimentally related to Human Endogenous RetroViruses (HERVs).

To characterize the MSRV-related HERV family and to test the hypothesis of a replication-competent HERV, we have investigated the expression of MSRV-related sequences in healthy tissues.

The expression of MSRV-related transcripts restricted to the placenta led to the isolation of overlapping cDNA clones from a cDNA library.

These cDNAs spanned a 7.6-kb region containing gag, pol, and env Genes; RU5 and U3R flanking sequences; a polypurine tract; and a Primer Binding Site (PBS).

As this PBS showed similarity to avian RetroVirus PBSs used by tRNATrp, this new HERV family was named HERV-W.

Several genomic elements were identified, one of them containing a complete HERV-W unit, spanning all cDNA clones.

Elements of this multicopy family were not replication competent, as gag and pol Open Reading Frames (ORFs) were interrupted by frameshifts and stop codons.

A complete ORF putatively coding for an envelope protein was found both on the HERV-W DNA prototype and within an RU5-env-U3R polyadenylated cDNA clone.

Placental expression of 8-, 3.1-, and 1.3-kb transcripts was observed, and a putative splicing strategy was described.

The apparently tissue-restricted HERV-W long terminal repeat expression is discussed with respect to Physiological and Pathological contexts.

Poorly-Known Virus
CoronaViruses, so named because of their sun-ray-like aspect, were discovered in the sixties.

The biology of these RNA Viruses is complex and poorly understood.

Known Pathogens
CoronaViruses are known Pathogens in veterinary medicine, causing disease states in several domestic species.

In human medicine, they can cause Benign Respiratory Infections, but few laboratories include CoronaViruses in their routine diagnostic tests.

Suspected Pathogens
There is some data in the literature suggesting CoronaViruses might be implicated in more severe diseases including Multiple Sclerosis, Necrotizing Enterocolitis, and Lower Respiratory Tract Infections, particularly in infants.

Improving Diagnostic Methods
Due to the lack of reliable and sensitive diagnostic techniques, it is impossible to date to correctly assess the medical impact of these ubiquitous and endemic Viruses.

Molecular biology techniques enabling detection of human CoronaVirus infections should be applied to verifying the suspected implication of these Viruses in diverse disease states.

Human HerpesVirus-6 (HHV-6) is a ßHerpesVirus that has been frequently associated with pediatric Encephalitis.

In 1995 Challoner et al reported that HHV-6 variant B (HHV-6B) was linked to Multiple Sclerosis (MS) due to the presence of Viral DNA and Antigen in the Oligodendrocytes surrounding MS Plaques.

These findings led us to examine HHV-6B's in vitro Tropism for primary Neural Cells. HIV-6B mediated cell-to-cell fusion in cultured adult OigodendroGlia.

Infection of Oigodendrocytes was further confirmed by transmission Electron Microscopy (EM), which showed the presence of IntraCellular HHV-6 particles, and by PCR for HHV-6 DNA.

However, the release of infectious Virus was low or undetectable in multiple experiments. Microglia were also susceptible to infection by HHV-6B, as demonstrated by an Antigen capture assay.

We did not detect infection of a differentiated Neuronal Cell line (NT2D).

Our findings suggest that HHV-6B infection of Oigodendrocytes and/or Microglia could potentially play a role in NeuroPathoGenesis.

• Comment in: J NeuroVirol 1998 Oct;4(5):471-3

CoronaVirus infections of rodents can cause diseases of the Central Nervous System characterized by Inflammatory DeMyelination.

The lesions mimick in many aspects the pathology of Multiple Sclerosis in humans and of other Neurological Diseases.

As an animal model for DeMyelination, we studied the MHV-JHM induced EncephaloMyelitis of Lewis rats. The PathoMorphological analysis revealed patterns of lesions which developed in stages.

1. Infected Oligodendrocytes were first destroyed by Necrosis.
2. Later stages were characterized by DeMyelinated plaques.
3. In the center of plaques, no Virus Antigen was found and Oigodendrocytes were mainly destroyed by Apoptosis.
4. At the edge of plaques, Virus Antigen was expressed in parallel to infiltrations consisting of Lymphocytes and Macrophages.

The prevailing mechanisms leading to DeMyelination may change individually and during defined stages of the disease.

The transcriptional expression of ChemoAttractants and other mediators of Inflammation was studied by semiquantitative RT-PCR.

Virus induced inflammatory DeMyelination was accompanied by high expression of a relatively novel Cytokine, the Endothelial Monocyte Activating PolyPeptide II (EMAP II).

By ImmunoCytoChemistry, EMAP II was detected in Parenchymal Microglia located both within the lesions and in unaffected areas.

Furthermore, the level of transcriptional expression of the regulatory Calcium binding S100 proteins MRP8, MRP14 and CP10 was associated with inflammatory DeMyelination.

And expression of IFN , IL-2, TNF , and iNOS.

Multiple Sclerosis is an Immune-mediated DeMyelinating disease of unknown etiology that presents with either a Chronic/Progressive or Relapsing/Remitting clinical course.

Theiler's Murine EncephaloMyelitis Virus-induced DeMyelinating Disease (TMEV-IDD) and Relapsing/Remitting Experimental AutoImmune EncephaloMyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4⁺ T-Cell-mediated DeMyelinating models that recapitulate the Multiple Sclerosis Disease phenotypes.

To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of Pro- and AntiInflammatory Cytokine mRNA expression in the Central Nervous System (CNS) and the phenotype of the inflammatory MonoNuclear infiltrates.

TMEV-infected SJL/J mice expressed IFN-, TNF-, IL-10, and IL-4 mRNA.

During the preclinical phase, and their levels continued to increase throughout the duration of the Chronic/Progressive disease course.

These data correlated with the continued presence of both CD4⁺ T-Cells and F4/80+ Macrophages within the CNS infiltrates.

In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory Cytokines, IFN-.

And TNF-, with expression peaking at the height of the acute phase and relapse(s).

This pattern correlated with dynamic changes in the CD4⁺ T-Cell and F4/80⁺ Macrophage populations during Relapsing/Remitting disease progression.

Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease.

Whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease.

These data suggest that the kinetics of Cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.

TO subgroup strains of Theiler's Murine EncephaloMyelitis Virus (TMEV) induce a persistent Central Nervous System infection and DeMyelinating disease in mice.

This disease serves as an experimental model of Multiple Sclerosis (MS) because the two diseases have similar Inflammatory White Matter pathologies and because the Immune System appears to mediate DeMyelination in both processes.

We previously reported (H. H. Chen, W. P. Wong, L. Zhang, P. L. Ward, and R. P. Roos, Nat. Med. 1:927-931, 1995) that TO subgroup strains use an alternative initiation codon (in addition to the AUG used to synthesize the PicornaVirus polyprotein from one long open reading frame).

To translate L*, a novel protein that is out of frame with the polyprotein and which plays a key role in the DeMyelinating Disease.

We now demonstrate that L* has AntiApoptotic activity in Macrophage Cells and is critical for Virus persistence.

The AntiApoptotic action of L* as well as the differential translation of L* and Virion capsid proteins may foster Virus persistence in Macrophages and interfere with Virus clearance.

The regulation of Apoptotic activity in Inflammatory Cells may be important in the PathoGenesis of TMEV-induced DeMyelinating Disease as well as MS.

RetroViruses are suspected to be involved in the PathoGenesis of AutoImmune Diseases, such as Multiple Sclerosis (MS).

Here, we describe a complete cartography of a novel human endogenous RetroViral sequence with a pol domain which shares a high homology with the pol sequence of the Multiple Sclerosis associated RetroVirus (MSRV).

Since this new endogenous RetroViral sequence is located in the close vicinity of the locus of the human Gene coding for the T-Cell receptor (TcR) and d chains on Chromosome 14, it could be of potential interest for the understanding of MS PathoGenesis.

This hypothesis for the PathoGenesis of Multiple Sclerosis is based upon assumptions about the response of the T-Cell repertoire to Pathogens.

Immunologic and Epidemiologic observations of several conditions suggest that activation of T-Cells formed in early life mediate injury to the Central Nervous System.

Early in life, selection of Lymphocytes by the Thymus produces a weakly AutoReactive T-Cell repertoire which, with the help of transient maternally-derived defenses, recognizes Pathogens.

These responses later are supplemented by Pathogen-specific responses, acquired as microbes are encountered. As the Thymus involutes, the diversity of Pathogen-specific responses to microbial Epitopes is progressively fixed.

Reduced and delayed Pathogen exposure, common in developed societies, limits the repertoire of Memory T-Cells, which can efficiently eliminate Pathogens.

Due to their small number, Pathogen-specific Lymphocytes which mature ExtraThymically may not be able to rapidly eliminate most Pathogens, and without the editing of the Thymus, they may be AutoReactive.

In this setting, novel Pathogens with Epitopes mimicking Myelin may elicit a T-Cell response which is AutoReactive. Peptides of common microbes are known to activate T-Cells recognizing dominant Antigens of Myelin.

It is postulated that at the equator, intense, non-seasonal encounters with microbes elicit an Immune repertoire that produces resistance to AutoImmunity, while, in temperate climates, moderate, seasonal exposures increase susceptibility to it.

The differences in responses to microbes between populations with a low or high prevalence of Multiple Sclerosis suggests that T-Cell repertoires are divergent in these groups.

An exuberant innate response, postulated to diminish as the load of enteric microbes falls and sanitation improves in relation to the distance from the equator, may increase resistance to Multiple Sclerosis by eliminating the need for T-Cell activation.

Human HerpesVirus-6 and respiratory Syncytial Virus are possible prototypes of microbes which activate Myelin-directed T-Cells.

Multiple Sclerosis (MS) is an inflammatory DeMyelinating Disease of the Central Nervous System, and the most common Neurological Disease affecting young adults. Multiple Sclerosis is a clinically heterogeneous disorder.

It is believed to be an AutoImmune Disease, with Cell-Mediated and Humoral Response directed against Myelin proteins.

This hypothesis largely comes from pathological parallels with an animal model, Experimental AutoImmune EncephaloMyelitis (EAE).

AutoImmunity to Myelin proteins in humans may be inadvertently triggered by microbes which have structural homologies with Myelin Antigens (Molecular Mimicry).

As with other AutoImmune Diseases, susceptibility to MS is associated with certain MHC Genes/Haplotypes.

Full Genomic screening of mutiplex families has underscored the role for MHC Genes as exerting moderate but the most significant effects in susceptibility.

The primary target AutoAntigen in MS has yet to be definitively identified, but as well as the major Myelin proteins (MBP, PLP), it is now clear that minor Myelin components, such as Myelin Oligodendrocyte Glycoprotein (MOG) may play a primary role in disease initiation.

This review examines the current knowledge about the Etiology and PathoGenesis of MS, and the important similarities with EAE.