Journal of Neuroimmunology 266 (2014) 87–88
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Letter to the Editor Multiple sclerosis-associated retrovirus and related human endogenous retrovirus-W in patients with multiple sclerosis Keywords: Multiple sclerosis Multiple sclerosis-associated retrovirus Human endogenous retrovirus-W Healthy carriers Pathogenesis Peripheral blood leucocytes
The recent literature review published in the Journal of Neuroimmunology by Hon et al. (2013) concerning multiple sclerosis associated retrovirus (MSRV) and human endogenous retrovirus-W (HERV-W) in patients with multiple sclerosis contains a number of errors and a fundamental logical misconception. We consider that we should bring this to the readers' attention in order to avoid misinterpretation of the current literature. One of the search terms used by Hon et al., to conduct the literature search, was “MSRW/HERV-W”. Use of this search term will fail to locate articles because the correct abbreviation is MSRV, not MSRW. The authors incorrectly state that Arru et al. (2007) reported detection of MSRV pol sequences in the cerebrospinal fluid (CSF) of 40% of healthy controls. The 40% figure in Arru et al. actually refers to the prevalence of MSRV pol sequences in patients with other neurological diseases (OND) rather than in healthy controls, in whom the prevalence was much lower. As reviewed by Dolei and Perron (2009), the presence/ load of extracellular MSRV was found increased repeatedly and independently in the blood and CSF of MS cohorts (prevalence in plasma, 53%–100%) of Caucasians from France, Sardinia, Northern Italy, Poland, Sweden, Spain and South Africa. MSRV viraemia also occurred in OND patients, but the frequency of MSRV detection was significantly lower than in MS, and MSRV load was significantly associated with MS in all ethnic groups studied; as for healthy controls, a meta-analysis from six independent studies showed that a mean of 8.9% ± 6.2% of Caucasian blood donors had circulating virionic MSRV/HERV-W RNA. At several places in the text, including the last sentence of the Abstract and the concluding sentence of the review, Hon et al. state that because MSRV/HERV-W expression is not completely restricted to patients with MS, it is “therefore an unlikely cause of the disease”. Indeed, this appears to be the major conclusion of the review. In our opinion, this conclusion is over-simplistic and clearly represents a logical non sequitur. If, as Hon et al. appear to believe, it were true that detection of an agent in a proportion of the healthy population meant that the agent was not or was unlikely to be the cause of disease, then we would have to dismiss many well established pathogens and the entire concept of asymptomatic infection. The human retrovirus HTLV-1 for example causes disease (adult T-cell leukemia/lymphoma or HTLV-I-associated myelopathy) in only a small proportion of those infected and the vast majority remain lifelong asymptomatic carriers (Gonçalves et al., 2010). Similarly, a significant proportion of healthy individuals are carriers of methicillin resistant Staphylococcus aureus (MRSA), a pathogen well known to be capable 0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2013.11.009
of causing life-threatening sepsis (Stefani et al., 2012). Environmental risk factors provide many other illustrations of this false logic; smoking is an incontrovertible cause of lung cancer and yet smoking is prevalent in a significant proportion of the healthy population. The majority of the studies reviewed by Hon et al. provide evidence of an association between MSRV/HERV-W expression and multiple sclerosis, but they were not intended to prove causality. Young et al. (2013) have recently discussed the criteria required to establish causal connections between HERVs and disease. These include the development of animal models and attempts to modulate disease in man by blocking endogenous retroviral protein function with therapeutic antibody; both of these criteria are currently being addressed for MSRV (Curtin et al., 2012; Perron et al., 2013). The potential contribution of co-factors such as Epstein–Barr virus (EBV), which are known to activate MSRV/HERV-W, should also be considered in this context (Mameli et al., 2012; Mameli et al., 2013). References Arru, G., Mameli, G., Astone, V., Serra, C., Huang, Y.-M., Link, H., Fainardi, E., Castellazzi, M., Granieri, E., Fernandez, M., Villoslada, P., Fois, M., Sanna, A., Rosati, G., Dolei, A., Sotgiu, S., 2007. Multiple sclerosis and HERV-W/MSRV: a multicentric study. Int. J. Biomed. Sci. 3, 292–297. Curtin, F., Lang, A.B., Perron, H., Laumonier, M., Vidal, V., Porchet, H.C., Hartung, H.P., 2012. GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study. Clin. Ther. 34, 2268–2278. Dolei, A., Perron, H., 2009. The multiple sclerosis-associated retrovirus and its HERV-W endogenous family: a biological interface between virology, genetics, and immunology in human physiology and disease. J. Neurovirol. 15, 4–13. Gonçalves, D.U., Proietti, F.A., Ribas, J.G., Araújo, M.G., Pinheiro, S.R., Guedes, A.C., Carneiro-Proietti, A.B., 2010. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin. Microbiol. Rev. 23, 577–589. Hon, G.M., Erasmus, R.T., Matsha, T., 2013. Multiple sclerosis-associated retrovirus and related human endogenous retrovirus-W in patients with multiple sclerosis: a literature review. J. Neuroimmunol. 263, 8–12. Mameli, G., Poddighe, L., Mei, A., Uleri, E., Sotgiu, S., Serra, C., Manetti, R., Dolei, A., 2012. Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS One 7, e44991. Mameli, G., Madeddu, G., Mei, A., Uleri, E., Poddighe, L., Delogu, L.G., Maida, I., Babudieri, S., Serra, C., Manetti, R., Mura, M.S., Dolei, A., 2013. Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein-Barr virus latency: the missing link with multiple sclerosis? PLoS One 8, e78474. Perron, H., Dougier-Reynaud, H.L., Lomparski, C., Popa, I., Firouzi, R., Bertrand, J.B., Marusic, S., Portoukalian, J., Jouvin-Marche, E., Villiers, C.L., Touraine, J.L., Marche, P.N., 2013. Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice. PLoS One 8, e80128. Stefani, S., Chung, D.R., Lindsay, J.A., Friedrich, A.W., Kearns, A.M., Westh, H., Mackenzie, F.M., 2012. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int. J. Antimicrob. Agents 39, 273–282. Young, G.R., Stoye, J.P., Kassiotis, G., 2013. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis. Bioessays 35, 794–803.
Antonina Dolei Department of Biomedical Sciences, University of Sassari, viale San Pietro 43B, 07100 Sassari, Italy Corresponding author. Tel.: +39 3204299685; fax: +39 079212345. E-mail address: [email protected]. Jeremy A. Garson Research Department of Infection, Division of Infection and Immunity, University College London, WC1E 6BT, United Kingdom
88
Letter to the Editor
Giannina Arru Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
Patrice N. Marche Institut Albert Bonniot, U823 INSERM/UJF, 38043 Grenoble Cedex 09, France
Mario Clerici Department of Biomedical Sciences and Technologies, University of Milan, Via Fratelli Cervi 93, 20090 Segrate-Milan, Italy Laboratory of Molecular Medicine and Biotechnologies, Don C. Gnocchi ONLUS Foundation, Via Capecelatro 66, 20148 Milan, Italy
Hervé Perron Geneuro SA, 18, ch des Aulx, CH-1228 Plan-les-Ouates, Switzerland Geneuro-Innovation, Bioparc Lyon-Laënnec, 60 Avenue Rockefeller, F 69008 Lyon, France Université Lyon-1, F 6900 Lyon, France
Raphaëlle Germi Department of Virology, University Hospital, 38043 Grenoble Cedex 09, France
8 November 2013
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Letter to the Editor Multiple sclerosis-associated retrovirus and related human endogenous retrovirus-W in patients with multiple sclerosis Keywords: Multiple sclerosis Multiple sclerosis-associated retrovirus Human endogenous retrovirus-W Healthy carriers Pathogenesis Peripheral blood leucocytes
The recent literature review published in the Journal of Neuroimmunology by Hon et al. (2013) concerning multiple sclerosis associated retrovirus (MSRV) and human endogenous retrovirus-W (HERV-W) in patients with multiple sclerosis contains a number of errors and a fundamental logical misconception. We consider that we should bring this to the readers' attention in order to avoid misinterpretation of the current literature. One of the search terms used by Hon et al., to conduct the literature search, was “MSRW/HERV-W”. Use of this search term will fail to locate articles because the correct abbreviation is MSRV, not MSRW. The authors incorrectly state that Arru et al. (2007) reported detection of MSRV pol sequences in the cerebrospinal fluid (CSF) of 40% of healthy controls. The 40% figure in Arru et al. actually refers to the prevalence of MSRV pol sequences in patients with other neurological diseases (OND) rather than in healthy controls, in whom the prevalence was much lower. As reviewed by Dolei and Perron (2009), the presence/ load of extracellular MSRV was found increased repeatedly and independently in the blood and CSF of MS cohorts (prevalence in plasma, 53%–100%) of Caucasians from France, Sardinia, Northern Italy, Poland, Sweden, Spain and South Africa. MSRV viraemia also occurred in OND patients, but the frequency of MSRV detection was significantly lower than in MS, and MSRV load was significantly associated with MS in all ethnic groups studied; as for healthy controls, a meta-analysis from six independent studies showed that a mean of 8.9% ± 6.2% of Caucasian blood donors had circulating virionic MSRV/HERV-W RNA. At several places in the text, including the last sentence of the Abstract and the concluding sentence of the review, Hon et al. state that because MSRV/HERV-W expression is not completely restricted to patients with MS, it is “therefore an unlikely cause of the disease”. Indeed, this appears to be the major conclusion of the review. In our opinion, this conclusion is over-simplistic and clearly represents a logical non sequitur. If, as Hon et al. appear to believe, it were true that detection of an agent in a proportion of the healthy population meant that the agent was not or was unlikely to be the cause of disease, then we would have to dismiss many well established pathogens and the entire concept of asymptomatic infection. The human retrovirus HTLV-1 for example causes disease (adult T-cell leukemia/lymphoma or HTLV-I-associated myelopathy) in only a small proportion of those infected and the vast majority remain lifelong asymptomatic carriers (Gonçalves et al., 2010). Similarly, a significant proportion of healthy individuals are carriers of methicillin resistant Staphylococcus aureus (MRSA), a pathogen well known to be capable 0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2013.11.009
of causing life-threatening sepsis (Stefani et al., 2012). Environmental risk factors provide many other illustrations of this false logic; smoking is an incontrovertible cause of lung cancer and yet smoking is prevalent in a significant proportion of the healthy population. The majority of the studies reviewed by Hon et al. provide evidence of an association between MSRV/HERV-W expression and multiple sclerosis, but they were not intended to prove causality. Young et al. (2013) have recently discussed the criteria required to establish causal connections between HERVs and disease. These include the development of animal models and attempts to modulate disease in man by blocking endogenous retroviral protein function with therapeutic antibody; both of these criteria are currently being addressed for MSRV (Curtin et al., 2012; Perron et al., 2013). The potential contribution of co-factors such as Epstein–Barr virus (EBV), which are known to activate MSRV/HERV-W, should also be considered in this context (Mameli et al., 2012; Mameli et al., 2013). References Arru, G., Mameli, G., Astone, V., Serra, C., Huang, Y.-M., Link, H., Fainardi, E., Castellazzi, M., Granieri, E., Fernandez, M., Villoslada, P., Fois, M., Sanna, A., Rosati, G., Dolei, A., Sotgiu, S., 2007. Multiple sclerosis and HERV-W/MSRV: a multicentric study. Int. J. Biomed. Sci. 3, 292–297. Curtin, F., Lang, A.B., Perron, H., Laumonier, M., Vidal, V., Porchet, H.C., Hartung, H.P., 2012. GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study. Clin. Ther. 34, 2268–2278. Dolei, A., Perron, H., 2009. The multiple sclerosis-associated retrovirus and its HERV-W endogenous family: a biological interface between virology, genetics, and immunology in human physiology and disease. J. Neurovirol. 15, 4–13. Gonçalves, D.U., Proietti, F.A., Ribas, J.G., Araújo, M.G., Pinheiro, S.R., Guedes, A.C., Carneiro-Proietti, A.B., 2010. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin. Microbiol. Rev. 23, 577–589. Hon, G.M., Erasmus, R.T., Matsha, T., 2013. Multiple sclerosis-associated retrovirus and related human endogenous retrovirus-W in patients with multiple sclerosis: a literature review. J. Neuroimmunol. 263, 8–12. Mameli, G., Poddighe, L., Mei, A., Uleri, E., Sotgiu, S., Serra, C., Manetti, R., Dolei, A., 2012. Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis. PLoS One 7, e44991. Mameli, G., Madeddu, G., Mei, A., Uleri, E., Poddighe, L., Delogu, L.G., Maida, I., Babudieri, S., Serra, C., Manetti, R., Mura, M.S., Dolei, A., 2013. Activation of MSRV-type endogenous retroviruses during infectious mononucleosis and Epstein-Barr virus latency: the missing link with multiple sclerosis? PLoS One 8, e78474. Perron, H., Dougier-Reynaud, H.L., Lomparski, C., Popa, I., Firouzi, R., Bertrand, J.B., Marusic, S., Portoukalian, J., Jouvin-Marche, E., Villiers, C.L., Touraine, J.L., Marche, P.N., 2013. Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice. PLoS One 8, e80128. Stefani, S., Chung, D.R., Lindsay, J.A., Friedrich, A.W., Kearns, A.M., Westh, H., Mackenzie, F.M., 2012. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int. J. Antimicrob. Agents 39, 273–282. Young, G.R., Stoye, J.P., Kassiotis, G., 2013. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis. Bioessays 35, 794–803.
Antonina Dolei Department of Biomedical Sciences, University of Sassari, viale San Pietro 43B, 07100 Sassari, Italy Corresponding author. Tel.: +39 3204299685; fax: +39 079212345. E-mail address: [email protected]. Jeremy A. Garson Research Department of Infection, Division of Infection and Immunity, University College London, WC1E 6BT, United Kingdom
88
Letter to the Editor
Giannina Arru Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
Patrice N. Marche Institut Albert Bonniot, U823 INSERM/UJF, 38043 Grenoble Cedex 09, France
Mario Clerici Department of Biomedical Sciences and Technologies, University of Milan, Via Fratelli Cervi 93, 20090 Segrate-Milan, Italy Laboratory of Molecular Medicine and Biotechnologies, Don C. Gnocchi ONLUS Foundation, Via Capecelatro 66, 20148 Milan, Italy
Hervé Perron Geneuro SA, 18, ch des Aulx, CH-1228 Plan-les-Ouates, Switzerland Geneuro-Innovation, Bioparc Lyon-Laënnec, 60 Avenue Rockefeller, F 69008 Lyon, France Université Lyon-1, F 6900 Lyon, France
Raphaëlle Germi Department of Virology, University Hospital, 38043 Grenoble Cedex 09, France
8 November 2013
