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Multiple sclerosis, retroviruses, and PCR. The HTLV-MS Working Group
Abstract
Previously reported serologic and polymerase chain reaction (PCR)-based findings have suggested an association between the human retrovirus, HTLV-I, and multiple sclerosis (MS). Due to the inherent ability of PCR to produce false-positive results, we developed a set of physical and procedural safeguards to minimize the possibility of molecular carryover. These were applied as part of a blinded, large-scale, multipopulation, multiplex PCR-based study designed to examine this issue of association. Our results do not support the hypothesis that HTLV-I, which plays a role in the pathogenesis of an encephalomyeloneuropathy, HTLV-II, or closely related agents are associated with MS. A concomitant review of the current literature supports this view.
... In particular, human herpes virus and retrovirus infections have been suggested and explored as possible candidates in the search for a cause of MS. 2 However, with the exception of HERV, the association of MS with human retroviruses appears to have been ruled out. 3 In contrast, evidence that human herpes virus infections, in particular Epstein-Barr virus (EBV) 4 and human herpes virus 6 (HHV-6), 5 may have pathogenic roles in MS is accumulating. ...
... The mean ARR was 1.03 in acyclovir compared with 1.57 in placebo-treated patients, that is a reduction in 34% (P = .083). If patients were grouped in low (0-2), medium (3)(4)(5) and high (≥6) relapse rates, the difference between acyclovir and placebo was significant (P = .017). The ARR during a 2-year prior baseline period was compared with that of the study period in patients who had at least 2 years of disease duration prior to randomization ( Figure 1). ...
There is increasing evidence that human herpes viruses and human endogenous retroviruses (HERV) are involved in the aetiology and pathogenesis of multiple sclerosis (MS). In order to acquire the ultimate evidence to confirm such a relationship, it is probably required to use specific antiviral drugs in clinical trials of MS. The results of published antiviral clinical trials in patients with MS are summarized in this review. None of them showed statistically significant effects on primary outcomes of disease activity or on disability development. However, given their small sample sizes, the strong trends and effects observed in subgroup analysis of antiherpes virus treatment in patients with MS warrant further studies. The possible involvement of HERV in MS is intriguing, and drugs have been developed that could reduce the impact of HERV in MS. However, larger studies are needed as the phase I and II trials were not designed to show clinical efficacy in MS.
... In MS, HTLV-I and HIV sequences are absent both by in situ hybridization and PCR. Antibodies to HTLV-I envelope proteins are also absent Hauser et al., 1986;Ehrlich et al., 1991). ...
Demyelination is a component of several viral diseases of humans. The best known of these are subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML). There are a number of naturally occurring virus infections of animals that involve demyelination and many of these serve as instructive models for human demyelinating diseases. In addition to the naturally occurring diseases, many viruses have been shown to be capable of producing demyelination in experimental situations. In discussing virus-associated demyelinating disease, the chapter reviews the architecture and functional organization of the CNS and considers what is known of the interaction of viruses with CNS cells. It also discusses the immunology of the CNS that differs in several important aspects from that of the rest of the body. Experimental models of viral-induced demyelination have also been considered. Viruses capable of producing demyelinating disease have no common taxonomic features; they include both DNA and RNA viruses, enveloped and nonenveloped viruses. The chapter attempts to summarize the important factors influencing viral demyelination, their common features, and possible mechanisms.
Multiple sclerosis (MS) is thought to be an autoimmune disease precipitated in genetically susceptible individuals by environmental factors. Recent attention has focused on the possible involvement of retroviruses in its aetiology. Initial experiments performed to detect the human retrovirus HTLV, in lymphocytes from 12 patients with MS, proved negative. In an attempt to identify a putative novel human retrovirus, a polymerase chain reaction (PCR) technique was developed which was capable of detecting a very diverse range of retroviruses including HIV, HTLV, MPMV and MMLV. This 'Pan-Retrovirus' PCR employed semi-nested, degenerate primers complementary to the two most highly conserved motifs of the pol gene. Using this technique a novel retroviral sequence, designated MSRV c-pol, was detected in the serum from a patient with a 12 year history of MS. This sequence was also present in retroviral particles which had been isolated from MS patient derived tissue cultures in France. MSRV is related to the endogenous retrovirus ERV-9, however it remains uncertain whether MSRV itself is an exogenous or endogenous retrovirus. By combining the 'Pan-Retrovirus' PCR with a hybridisation-based detection assay, MSRV c-pol RNA was detected in serum from 24 of 40 (60%) patients with MS but not in 30 controls; and in cerebrospinal fluid from 5 of 10 patients with MS but not in 10 other neurological disease controls. An MSRV specific RT-PCR assay was also developed. This detected virion-associated MSRV pol RNA in serum from 9 of 17 (53%) patients with clinically active MS (in all 6 of those not undergoing immunosuppressive treatment), compared with only 3 of 44 (7%) controls. A novel human retroviral sequence has been identified, and an association demonstrated between the presence of MSRV-RNA and MS. Further work will be required to determine the significance of MSRV in the aetiopathogenesis of this common neurological disease.
Major advances in understanding the complex processes that regulate the immune system have been achieved. Elucidating the causes of human diseases characterized by inappropriate activation of the immune system, however, remains an elusive goal. Chronic inflammatory diseases or autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), appear to involve multifactorial pathogenic mechanisms. A genetic basis for susceptibility is established by the observation that occurrence of autoimmune diseases is substantially increased among family members of patients and is often related to inheritance of various genes in the human major histocompatibility complex (MHC). For example, the incidence of SLE is elevated in individuals that express certain haplotypes of the D-regulated (DR) and class III (complement, C) regions of the MHC (Doherty et al., 1992; Reveille, 1992). Other factors are also involved since only a fraction of SLE patients have the common haplotypes, and the concordance rate for SLE in identical twins is only about 30% (Christian et al., 1975; Imamura et al., 1975; Arnett and Shulman, 1976; Block et al., 1976). Many autoimmune diseases afflict predomi-nantly women, suggesting that hormonal factors may contribute to disease development and progression (Alarcon, 1993; Carlsten and Tarkowski, 1993). Furthermore, Afro-Americans are afflicted with SLE approximately three times as frequently as Americans of European descent, but blacks living in Africa do not appear to develop the disease with the same prevalence as their European or American counterparts (Clark et al., 1993).
Objective. To investigate a possible association between human T cell leukemia/lymphoma virus type I (HTLV-I) and polymyositis (PM).
Methods. Sera and muscle biopsy samples from 9 Jamaican PM patients were compared with specimens from American HTLV-I–positive PM patients and normal controls. Sera were evaluated for HTLV antibodies by enzyme-linked immunosorbent assay and Western blot. The biopsy samples were analyzed for HTLV-I/II DNA by polymerase chain reaction and were also immunohistochemically stained for HTLV gp46 envelope protein.
Results. Seven of the 8 Jamaican PM patients from whom sera were available were HTLV-I seropositive. The muscle biopsies of all 9 Jamaican patients demonstrated severe lymphocytic infiltration, cellular degeneration, myofiber atrophy, and fibrosis. Each muscle biopsy specimen contained HTLV-I DNA. Two of 6 samples demonstrated intense staining for HTLV-I gp46 in many of the invading mononuclear cells and weak staining for HTLV-I gp46 in many of the invading mononuclear cells and weak staining in the adjacent myocytes. Two other specimens were weakly positive for gp46 in rare mononuclear cells. All control specimens were negative for the presence of HTLV-I DNA and protein.
Conclusion. HTLV-I is associated with an inflammatory muscle disease characterized by direct invasion of the affected muscle by HTLV-I–infected mononuclear cells.
The role of human spumaretrovirus (HSRV) infections in the pathogenesis of multiple sclerosis (MS) was investigated with recombinant HSRV env-specific enzyme-linked immunosorbent assay. The presence of HSRV antibodies was determined in pairs of serum and cerebrospinal fluid (CSF) samples from 60 MS patients. In 7 of these patients serial serum and CSF samples were obtained in relation to the clinical activity of the disease during a period of 2 years. No increased antibody reactivity was demonstrable in the MS population compared with 14 aseptic meningitis patients, 50 blood donors and 16 healthy controls. Slightly elevated levels of antibodies were demonstrable in serum and/or CSF in 4 MS patients but also in 1 patient with aseptic meningitis, 1 blood donor and 1 child. No marked serum or CSF HSRV antibody fluctuation was observed in the MS patients followed longitudinally. Thus, this study does not support the involvement of HSRV in the pathogenesis of MS.
Se ha estudiado mediante técnicas de unión al receptor (binding) el receptor de interleucina-1 (il-1r) en snc de ratón y rata. Se ha caracterizado la modulación de dicho receptor a través de los glucocorticoides (gc) en condiciones básales y de activación del sistema inmune (si), usando para esto último la administración periférica de lps y la inyección i.c. del virus de theiler (tmev). Tanto el lps, como el tmev, inducen, respectivamente, la secreción periférica o central de il-1. El tmev, además, produce una encefalomielitis en ratones susceptibles de la cepa sjl/j, usada como modelo animal de la esclerosis múltiple. Nuestros hallazgos confirman la existencia de un receptor central para il-1 en hipocampo de varias cepas de ratones. Dicho il-1r es escasamente modulado, en condiciones básales de activación del sí, por los gc, tanto in vivo como in vitro. La administración de lps produjo un descenso en la ocupación del il-1r, que no fue revertida por los gc. La inyección de tmev produjo también un descenso en la unión al il-1r en hipocampo en las fases iniciales de la enfermedad, cuando los animales estaban asintomáticos. Este descenso fue especifico de las cepas susceptibles a padecer la enfermedad y fue revertido por los gc.
The etiology of multiple sclerosis is linked to a variety of genetic and environmental factors. Both cell-mediated and humoral immune responses, triggered by extraneous or autoantigens, are likely to contribute to the pathogenesis of this disease. A greater insight into the fundamental cause of multiple sclerosis has been provided by the recognition that certain immune response genes are associated with an increased susceptibility to the disease. Such knowledge should provide new opportunities for selective therapeutic interventions.
Polymerase chain reaction analysis was used to investigate the possible role of human spumaretrovirus and oncoretroviruses (human T-cell lymphotropic virus types I [HTLV-I] and II [HTLV-II]) in multiple sclerosis. Eleven patients with relapsing-remitting multiple sclerosis in exacerbation and 11 normal blood donors were included in the study. Cerebrospinal fluid cells, peripheral blood mononuclear cells, and plasma were cocultured with allogeneic mononuclear cells for 6 weeks. Cultured cells were subjected to polymerase chain reaction analysis with primers selected for the pol and gag (human spumaretrovirus), pol and env (HTLV-I), and pol (HTLV-II) genes. Polymerase chain reaction was negative in all patient and blood donor control samples, whereas positive controls were consistently reactive with high sensitivity. No culture exhibited cytopathic effects and supernatants were negative for reverse transcriptase activity. Thus, our results do not support a role for these retroviruses in the pathogenesis of multiple sclerosis.
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