Retroviruses In Multiple Sclerosis Research Articles

Vitamin D, Epstein-Barr virus, and endogenous retroviruses in multiple sclerosis - facts and hypotheses

The pathogenesis of multiple sclerosis (MS) remains poorly understood. Presumably, MS is caused by multiple environmental, epigenetic, and genetic factors. Among them, human endogenous retroviruses (HERVs), Epstein-Barr virus (EBV) and vitamin D have been suggested to play a role in the pathogenesis and course of MS. Because vitamin D can affect the immune system and infections, it can be hypothesized that there is a close interplay between vitamins, EBV and ERV in the pathogenesis of MS. Here, we summarize the important data on vitamin D, including polymorphisms in genes related to vitamin D metabolism, EBV and ERV, in the pathogenesis of MS and create hypotheses regarding their interactions. Data indicate that vitamin D has a strong impact on viral infections and interferes with EBV infection, while EBV is capable of activating silent ERVs. We believe that EBV could be the missing link between vitamin D and ERV in MS pathogenesis.

The monoclonal antibody GNbAC1: targeting human endogenous retroviruses in multiple sclerosis.

Background:Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS). Despite improvements of immunomodulatory therapies in relapsing–remitting MS, the pathomechanisms of progressive disease are poorly understood and therapeutically addressed to date. A pathophysiological role for proteins encoded by human endogenous retroviruses (HERVs) has been proposed. GNbAC1 is a monoclonal antibody directed against the envelope protein of a HERV with postulated involvement in MS.Methods:This review addresses the treatment concept of GNbAC1, the design, preclinical and clinical development of the antibody, as published by November 2018. All four in-human trials (of which two addressed MS) are discussed.Conclusion:The treatment concept of GNbAC1 is appealing but remains controversial due to conflicting results regarding the hypothesized underlying pathomechanism. Anticipated immunomodulatory effects were not observed in clinical or pharmacodynamic analyses of the currently available data. However, a magnetic resonance imaging sign compatible with the remyelinating potential of GNbAC1 encouraged further development of this antibody in progressive MS. No relevant issues with tolerability or safety have been described to date.

Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation.

Multiple sclerosis is an immune‐mediated disease with an environmental component. According to a long‐standing but unproven hypothesis dating to initial descriptions of multiple sclerosis (MS) at the end of the 19th century, viruses are either directly or indirectly implicated in MS pathogenesis. Whether viruses in MS are principally causal or simply contributory remains to be proven, but many viruses or viral elements—predominantly Epstein‐Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV‐6) but also less common viruses such as Saffold and measles viruses—are associated with MS. Here, we present an up‐to‐date and comprehensive review of the main candidate viruses implicated in MS pathogenesis and summarize how these viruses might cause or lead to the hallmark demyelinating and inflammatory lesions of MS. We review data from epidemiological, animal and in vitro studies and in doing so offer a transdisciplinary approach to the topic. We argue that it is crucially important not to interpret “absence of evidence” as “evidence of absence” and that future studies need to focus on distinguishing correlative from causative associations. Progress in the MS‐virus field is expected to arise from an increasing body of knowledge on the interplay between viruses and HERVs in MS. Such interactions suggest common HERV‐mediated pathways downstream of viral infection that cause both neuroinflammation and neurodegeneration. We also comment on the limitations of existing studies and provide future research directions for the field.

The Etiology of Multiple Sclerosis: Genetic Evidence for the Involvement of the Human Endogenous Retrovirus HERV-Fc1

We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis.

Antibody reactivity against animal retroviruses in multiple sclerosis

A total of 27 MS patients and 82 controls were studied for presence of antibodies reacting with maedi-visna virus and bovine leukemia virus by means of 2 ELISA techniques. Furthermore, the differentiated antibody response against BLV antigens was evaluated by immunoblotting. People with elevated activities against MVV were detected in the MS group as well as controls. Elevated antibody activity against BLV as determined by biotinylated protein A and peroxidase-labelled streptavidin tended to occur more frequently in MS patients than in controls. No such difference was found, however, when peroxidase-conjugated antibodies against human kappa chain were used for detection of antibodies reacting with BLV. Immunoblotting revealed no difference between the MS and the control group when anti-kappa antibodies were used to detect antibody binding to BLV antigens. The protein A method revealed significantly decreased antibody activity against a BLV antigen with molecular weight of about 29 kD in MS compared with controls, whereas a significant rise in number of MS patients responding to a component of about 53 kD was observed. The differences between the 2 detection systems could be due to unspecific reactions. The present data indicate that MS patients exhibit an inhomogeneous and, in some cases elevated, antibody activity against BLV.

HERV-K113 Is Not Associated with Multiple Sclerosis in a Large Family-Based Study

Numerous studies have invoked a role for retroviruses in multiple sclerosis (MS). Most have identified human endogenous retroviruses (HERVs) as possible etiological agents. The majority of HERVs originate from ancestral infection and then become progressively disabled by mutations over millions of years of primate evolution. Their presence in 100% of healthy humans, together with the paucity of functional retroviral genes, argues strongly against a causal role in disease. Recently, a new class of insertionally polymorphic HERVs has been described that is present in only a proportion of the population. One of them, HERV-K113, is notable for open reading frames for all of its genes and is found in 0-28% of humans with widespread geographic and racial variation. Thus HERV-K113 is a credible candidate for causing disease in a manner comparable to infectious retroviruses. Genomic DNA samples from 951 patients with MS were tested for the presence of the HERV-K113 allele by PCR, with their unaffected parents (n = 1902) acting as controls. HERV-K113 provirus was found in 70 out of 951 (7.36%) patients with MS and was not significantly increased compared to the combined parent group (6.52%). The results do not support an association between this endogenous retrovirus and MS. This study also emphasizes the need for large cohorts with controls for race and geographic location when examining possible links between polymorphic HERVs and disease.

Comparative Expression of Human Endogenous Retrovirus-W Genes in Multiple Sclerosis

Human endogenous retroviruses (HERVs) have been associated with multiple sclerosis (MS) pathogenesis. Several related HERV-W sequences have been implicated in disease occurrence and progression; the MS retrovirus (MSRV) is one such element whose envelope protein has been recently demonstrated to be involved in innate immune pathogenesis. To distinguish MSRV from other HERV-W sequences we analyzed the relative abundance of individual HERV-W env sequences by employing a real-time PCR approach using specific oligonucleotide primers and tissue samples from MS and non-MS patients. Our analyses reveal that ERVWE1 env-encoding DNA and RNA exhibited increased detection (p < 0.05) and expression (p < 0.01) in the brains of MS patients. Similarly, ERVWE1 env transcripts were inducible in glial cells (p < 0.05), while comparable changes in MSRV abundance were not observed. These results indicate that individual HERVs might have distinct roles in MS pathogenesis.

Identification and Phylogenetic Analysis of Schizophrenia Associated Retrovirus (SZRV) Element in the Human GenBank Database

A significant proportion of the human genome consists of interspersed repetitive DNA sequences. One type of repetitive DNA elements is human endogenous retroviruses (HERVs), representing about 1% of the human genome. Their structures closely resemble those of retroviruses, and include internal sequences with homology to gag, pol, and env open reading frames (ORFs) flanked by long terminal repeats (LTRs). The internal sequences contain several transcriptional regulatory sequences [5]. Human genome mapping research has discovered “sequences” of HERVs (i.e. parts of their RNA), which are present in multiple copies and become part of human genome. HERV elements are generally do not cause any problem in their human host, but they may act as an agent of genome change and a potential source of genetic variation associated with certain diseases. A few HERV elements, such as schizophrenia-associated retrovirus (SZRV; schizophrenia), multiple-sclerosis retrovirus (MSRV; multiple sclerosis), endogenous retrovirus-9 (ERV-9) and HERV-W, have been isolated and associated with patients having specific diseases. SZRV element includes pol gene as its part and has 3 subtypes; SZRV-1, -3, and -4 [1, 2, 4]. Schizophrenia is a serious neuropsychiatric disease with uncertain etiology. Involvement of endogenous and/or exogenous retroviral-related sequences in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. The three SRZV subtypes were reported as candidate etiologic agents [3]. However, their distribution in the human genome has not been clearly identified. The aim of this study is to identify the distribution of the homologous sequences of SZRV subtypes in human genome, and to perform their phylogenetic analysis to find their association with SZRV element using the neighbor-joining method.

Detection of a gliotoxic activity in the cerebrospinal fluid from multiple sclerosis patients

We recently showed that peripheral blood cell supernatants from multiple sclerosis (MS) patients, containing reverse transcriptase activity and retroviral RNA from the newly human identified multiple sclerosis retrovirus (MSRV), also secrete a cytotoxin which induces death of primary mouse cortical glial cells. We have hypothesized that macrophages could release this cytotoxin in the cerebrospinal fluid. The cerebrospinal fluid cytotoxicity from 166 patients with various neurological diseases (including MS patients) was tested on glial cells in vitro. Our bioassay shows that a glial cytotoxic activity is significantly present in cerebrospinal fluid from patients with relapsing-remitting MS at relapse. Since this cytotoxic activity seems to correlate with active cases of MS, it may represent a critical pathogenic factor in the neuropathology of MS.

Cell cultures and associated retroviruses in multiple sclerosis. Collaborative Research Group on MS.

Retroviral particles associated with reverse transcriptase (RT) activity in cell-cultures from MS patients have been reported by different groups. Cell-cultures have been used for the study and characterization of the corresponding retroviral genome which we have shown is related to ERV9 in the pol region. Previously unpublished details of a study with monocyte cultures are presented together with observations on leptomeningeal and choroid-plexus cultures. The generation of self-transformed cultures after inhibition of interferon, followed by the loss of retroviral expression and recurrent apoptosis, is analyzed. Retroviral particles with RT-activity are produced in monocyte cultures with an apparent correlation with MS disease activity. However, though leptomeningeal and choroid plexus cells from MS can be passaged for a limited period, their evolution in vitro is not compatible with stable retroviral expression. These culture limitations greatly hampered progress on the elucidation of the retroviral genome sequence.

Discussion from the 4th International Symposium on Retrovirus in Multiple Sclerosis and Related Diseases

Discussion from the 4th International Symposium on Retrovirus in Multiple Sclerosis and Related Diseases

Search for a retrovirus in multiple sclerosis by enzymatic amplification of DNA from brain capillaries, brain tissue and mononuclear cells from peripheral blood.

Attempts were made to trace a possible retrovirus in multiple sclerosis (MS) by means of polymerase chain reaction. The primers derived from conserved sequences in the genome of human T cell leukemia/lymphoma virus type I (HTLV-I) and the amplifications were carried out at varying stringency conditions (i.a. annealing at low stringency to enhance the cross-reactivity of the primers). Included in the study were samples of DNA from brain capillaries (five MS patients), brain tissue (three MS patients) and peripheral blood mononuclear cells (three MS patients). Using an HTLV-I derived probe at relaxed conditions of stringency, hybridization signals were not recorded with amplified material from any of these samples. Aspects of infections with neurotropic retroviruses that could be relevant to the search for a retrovirus in MS are reviewed.

On the possible involvement of retrovirus in multiple sclerosis and MS-like diseases

On the possible involvement of retrovirus in multiple sclerosis and MS-like diseases

Is multiple sclerosis caused by a dual infection with retrovirus and Epstein-Barr virus?

Although the etiology of multiple sclerosis is as yet unknown, epidemiological observations strongly point toward one or more infectious agent(s) being involved in the disease. In recent years some studies have indicated involvement of retrovirus in multiple sclerosis (MS). However, an intrafamilial epidemiological study revealed that MS and the known human retroviruses had a divergent epidemiology. Some studies have shown the association of Epstein-Barr virus (EBV) with MS and one recent study revealed dual infection by retrovirus and EBV in a cell line established from a patient with an MS-like disease. Our hypothesis for the development of MS and MS-like diseases is that a hitherto uncharacterized retrovirus is the etiological agent, but development of neurologic disease is related to or even dependent on a delayed EBV infection. The dual infection hypothesis is analyzed and found to be consistent with the epidemiological characteristics of MS.

Antibody to reverse transcriptase of human retroviruses in multiple sclerosis

HTLV-1, HIV-1 and HIV-2 western blot analysis of sera from patients with multiple sclerosis (MS), from patients with other neurological diseases and from blood donors, revealed a rather frequent cross-reactivity with retroviral proteins in the MS group, though no patient was positive with the corresponding specific ELISA serology. Statistical analysis revealed a significant difference between the MS group and the two control groups for HIV-1 and HIV-2 reverse transcriptase fragments and for HTLV-1 p24. The general significance of these observations is discussed in the light of a retroviral hypothesis for the aetiology of MS. It is suggested that, if a retrovirus is present in MS patients, it does not necessarily belong to the HTLV sub-family and could as well be a lentivirus, like Visna virus, the causative agent of a demyelinating disease in sheep which is one--natural--model for MS.

On the possible involvement of a retrovirus in multiple sclerosis

On the possible involvement of a retrovirus in multiple sclerosis

On the possible involvement of a retrovirus in multiple sclerosis

On the possible involvement of a retrovirus in multiple sclerosis

Retrovirus in multiple sclerosis

Presence of cytopathic effect and enzyme reverse transcriptase in cultures of peripheral blood mononuclear cells is described in 2 of 15 patients with multiple sclerosis and none of healthy controls. These findings might indicate: the presence of a new human retrovirus in these individuals, despite the low detection rate, and the shortcomings inherent in methodology used for detection of known human retroviruses in the study of new groups of diseases, such as those with possible autoimmune background.

Bone marrow derived cells express human T-cell lymphotropic virus type I (HTLV-I)-related antigens in patients with multiple sclerosis.

Mononuclear cells in peripheral blood (PB) and cerebrospinal fluid (CSF) of seven patients and lymph nodes of three patients with clinically definite multiple sclerosis (MS) expressed antigens that reacted with monoclonal antibodies (MoAb) specific for HTLV-I p19 and p24 gag proteins. The labelled cells were visualized with immunoperoxidase staining and indirect immunofluorescence and identified at the ultrastructural level with immunogold technique. The frequency of these cells was low, ranging from 0.1% to less than 0.01% in blood. In CSF it was approximately 10 times lower. Cells reacting with anti-p19 Ab were found in all MS samples, whereas cells reacting with anti-p24 Ab were found in 3 out of 6 blood samples and in 3 out of 7 CSF samples. All lymph nodes (3/3) obtained from MS patients contained cells that reacted with anti-HTLV-I. p19 and p24 Ab. Cells reacting with the same AB were detected in blood of one out of 12 healthy controls. Stained cells were irregular, distinctly larger than lymphocytes, and had abundant cytoplasm, suggesting that they may be monocytes/macrophages. Immunogold particles were located in vacuole-like structures in the cytoplasm. The presence in MS patients of cells that react with HTLV-I Ab indicates that a human retroviral genome is being expressed, and suggests that a virus may be present. Our data support a role for a human retrovirus in multiple sclerosis.

Reply to: Lack of evidence for involvement of known human retroviruses in multiple sclerosis

Reply to: Lack of evidence for involvement of known human retroviruses in multiple sclerosis