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Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids

Kochs, Georg; Haller, Otto
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 02/03/1999 EN
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27.63%
Interferon-induced human MxA protein belongs to the dynamin superfamily of large GTPases. It exhibits antiviral activity against a variety of RNA viruses, including Thogoto virus, an influenza virus-like orthomyxovirus transmitted by ticks. Here, we report that MxA blocks the transport of Thogoto virus nucleocapsids into the nucleus, thereby preventing transcription of the viral genome. This interaction can be abolished by a mAb that neutralizes the antiviral activity of MxA. Our results reveal an antiviral mechanism whereby an interferon-induced protein traps the incoming virus and interferes with proper transport of the viral genome to its ultimate target compartment within the infected cell.

Expression of Human MxA Protein in Mosquito Cells Interferes with LaCrosse Virus Replication

Miura, Tanya A.; Carlson, Jonathan O.; Beaty, Barry J.; Bowen, Richard A.; Olson, Ken E.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2001 EN
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27.63%
Human MxA protein inhibits LaCrosse virus (LAC virus; family Bunyaviridae) replication in vertebrate cells and MxA-transgenic mice. LAC virus is transmitted to humans by Aedes triseriatus mosquitoes. In this report, we have shown that transfected mosquito cells expressing the human MxA cDNA are resistant to LAC virus but permissive for Sindbis virus (family Togaviridae) infection.

Human MxA protein inhibits tick-borne Thogoto virus but not Dhori virus.

Frese, M; Kochs, G; Meier-Dieter, U; Siebler, J; Haller, O
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1995 EN
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27.92%
Thogoto and Dhori viruses are tick-borne orthomyxoviruses infecting humans and livestock in Africa, Asia, and Europe. Here, we show that human MxA protein is an efficient inhibitor of Thogoto virus but is inactive against Dhori virus. When expressed in the cytoplasm of stably transfected cell lines, MxA protein interfered with the accumulation of Thogoto viral RNA and proteins. Likewise, MxA(R645), a mutant MxA protein known to be active against influenza virus but inactive against vesicular stomatitis virus, was equally efficient in blocking Thogoto virus growth. Hence, a common antiviral mechanism that is distinct from the antiviral action against vesicular stomatitis virus may operate against both influenza virus and Thogoto virus. When moved to the nucleus with the help of a foreign nuclear transport signal, MxA(R645) remained active against Thogoto virus, indicating that a nuclear step of virus replication was inhibited. In contrast, Dhori virus was not affected by wild-type or mutant MxA protein, indicating substantial differences between these two tick-transmitted orthomyxoviruses. Human MxB protein had no antiviral activity against either virus.

Enhanced virus resistance of transgenic mice expressing the human MxA protein.

Pavlovic, J; Arzet, H A; Hefti, H P; Frese, M; Rost, D; Ernst, B; Kolb, E; Staeheli, P; Haller, O
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1995 EN
Relevância na Pesquisa
27.76%
MxA is a GTPase that accumulates to high levels in the cytoplasm of interferon-treated human cells. Expression of MxA cDNA confers to transfected cell lines a high degree of resistance against several RNA viruses, including influenza, measles, vesicular stomatitis, and Thogoto viruses. We have now generated transgenic mice that express MxA cDNA in the brain and other organs under the control of a constitutive promoter. Embryonic fibroblasts derived from the transgenic mice were nonpermissive for Thogoto virus and showed reduced susceptibility for influenza A and vesicular stomatitis viruses. The transgenic animals survived challenges with high doses of Thogoto virus by the intracerebral or intraperitoneal route. Furthermore, the transgenic mice were more resistant than their nontransgenic littermates to intracerebral infections with influenza A and vesicular stomatitis viruses. These results demonstrate that MxA is a powerful antiviral agent in vivo, indicating that it may protect humans from the deleterious effects of infections with certain viral pathogens.

Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein.

Frese, M; Kochs, G; Feldmann, H; Hertkorn, C; Haller, O
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1996 EN
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27.63%
Viruses of the Bunyaviridae family cause a variety of diseases ranging from uncomplicated fever to potentially lethal encephalitis and hemorrhagic fever. Little is known about the factors determining pathogenicity in the vertebrate host. Interferons have been reported to be inhibitory, but their mode of action against members of the Bunyaviridae has not yet been elucidated. The interferon-induced MxA protein encoded on human chromosome 21 is a large GTPase with antiviral activity against distinct negative-strand RNA viruses, notably influenza viruses. Here we show that MxA inhibits representative members of the Bunyaviridae family by interacting with an early step of virus replication. When constitutively expressed in stably transfected Vero cells, MxA prevented the accumulation of viral transcripts and proteins of Hantaan virus (genus Hantavirus). Other members of the family such as La Crosse virus (genus Bunyavirus) and Rift Valley fever virus and sandfly fever virus (both genus Phlebovirus) were likewise inhibited, and virus titers were reduced up to 10(4)-fold. Our data indicate that humans have evolved a mechanism of controlling these viruses irrespective of differences in viral coding strategies.

Inhibition of vesicular stomatitis virus mRNA synthesis by human MxA protein.

Staeheli, P; Pavlovic, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1991 EN
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27.98%
The interferon-induced human MxA protein inhibits the multiplication of influenza virus and vesicular stomatitis virus (VSV) by an unknown mechanism. Here we show that MxA protein interferes with VSV mRNA synthesis. Transfected Swiss 3T3 mouse cells constitutively expressing MxA protein and control cells were infected with VSV, and viral RNA and protein synthesis was monitored. Viral macromolecules were very abundant in control cells at 4 h postinfection, whereas the pools of VSV proteins and RNAs were more than 50-fold reduced in cells expressing MxA. To determine whether MxA inhibited VSV primary transcription, we infected the cells in the presence of the protein synthesis inhibitor cycloheximide and measured the pools of the five viral mRNAs at 4 h postinfection. VSV L mRNA concentration was more than 20-fold reduced, VSV G mRNA concentration was about 10-fold reduced, and the other viral mRNAs were three- to fivefold less abundant in MxA-expressing cells than in control cells. Our results thus indicate that MxA interferes with normal VSV mRNA synthesis either directly by inhibiting the activity of the viral polymerase complex or indirectly by reducing the stability of the VSV mRNAs.

Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein.

Pavlovic, J; Zürcher, T; Haller, O; Staeheli, P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1990 EN
Relevância na Pesquisa
27.98%
MxA and MxB are interferon-induced proteins of human cells and are related to the murine protein Mx1, which confers selective resistance to influenza virus. In contrast to the nuclear murine protein Mx1, MxA and MxB are located in the cytoplasm, and their role in the interferon-induced antiviral state was unknown. In this report we show that transfected cell lines expressing MxA acquired a high degree of resistance to influenza A virus. Surprisingly, MxA also conferred resistance to vesicular stomatitis virus. Expression of MxA in transfected 3T3 cells had no effect on the multiplication of two picornaviruses, a togavirus, or herpes simplex virus type 1. Treatment of MxA-expressing cells with antibodies to mouse alpha-beta interferon did not abolish the resistance phenotype. The conclusion that resistance to influenza virus and vesicular stomatitis virus was due to the specific action of MxA is further supported by the observation that transfected 3T3 cell lines expressing the related MxB failed to acquire virus resistance.

MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups.

Li, Y; Youssoufian, H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/12/1997 EN
Relevância na Pesquisa
27.76%
Fanconi anemia (FA) consists of a group of at least five autosomal recessive disorders that share both clinical (e.g., birth defects and hematopoietic failure) and cellular (e.g., sensitivity to cross-linking agents and predisposition to apoptosis) features with each other. However, a common pathogenetic link among these groups has not been established. To identify genetic pathways that are altered in FA and characterize shared molecular defects, we used mRNA differential display to isolate genes that have altered expression patterns in FA cells. Here, we report that the expression of an interferon-inducible gene, MxA, is highly upregulated in cells of FA complementation groups A, B, C, and D, but it is suppressed in FA group C cells complemented with wild-type FAC cDNA as well as in non-FA cells. A posttranscriptional mechanism rather than transcriptional induction appears to account for MxA overexpression. Forced expression of MxA in Hep3B cells enhances their sensitivity to mitomycin C and induces apoptosis, similar to the FA phenotype. Thus, MxA is a downstream target of FAC and is the first genetic marker to be identified among multiple FA complementation groups. These data suggest that FA subtypes converge onto a final common pathway...

Quantification of Different Human Alpha Interferon Subtypes and Pegylated Interferon Activities by Measuring MxA Promoter Activation

François, Catherine; Bernard, Isabelle; Castelain, Sandrine; Charleston, Bryan; Fray, Martin D.; Capiod, Jean-Claude; Duverlie, Gilles
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/2005 EN
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27.63%
Alpha interferons (α-IFNs) are potent biologically active proteins synthesized and secreted by somatic cells during viral infection. Quantification of α-IFN concentrations in biological samples is used for diagnosis. More recently, recombinant IFNs have been used as antiviral, antiproliferative, and immunomodulatory therapeutic agents, and particularly for the treatment of chronic hepatitis C virus infection. For this purpose, IFN has recently been coupled to polyethylene glycol (PEG) to improve the pharmacokinetic properties. The measure of α-IFN in biological samples from treated patients could be useful to ensure compliance to therapy and the true IFN activity in relation to viral decay during follow-up. In particular, it could be used to monitor the PEG-IFN concentration in patients treated for hepatitis C virus infection. The most frequently used test is a bioassay based on the antiviral property of the IFN, but the assay is not highly reproducible. Here, we present a reporter test based on MxA promoter activation of chloramphenicol acetyltransferase expression (Mx-CAT). MxA is an antiviral protein induced and tightly regulated by α-IFN. The Mx-CAT assay showed good reproducibility of 15% and was suitable to quantify PEG-IFN and numerous other α-IFN subtypes as well...

Inhibition of a Large Double-Stranded DNA Virus by MxA Protein▿

Netherton, Christopher L.; Simpson, Jennifer; Haller, Otto; Wileman, Thomas E.; Takamatsu, Haru-Hisa; Monaghan, Paul; Taylor, Geraldine
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.92%
Increasing evidence points to the importance of the interferon (IFN) response in determining the host range and virulence of African swine fever virus (ASFV). Infection with attenuated strains of ASFV leads to the upregulation of genes controlled by IFN pathways, including myxovirus resistance (Mx) genes that are potent effectors of the antiviral state. Mx gene products are known to inhibit the replication of many negative-sense single-stranded RNA viruses, as well as double-stranded RNA viruses, positive-sense single-stranded RNA viruses, and the reverse-transcribing DNA virus hepatitis B virus. Here, we provide data that extend the known range of viruses inhibited by Mx to include the large double-stranded DNA viruses. Stably transfected Vero cells expressing human MxA protein did not support ASFV plaque formation, and virus replication in these cells was reduced 100-fold compared with that in control cells. In contrast, ASFV replication in cells expressing MxB protein or a mutant MxA protein was similar to that in control Vero cells. There was a drastic reduction in ASFV late protein synthesis in MxA-expressing cells, correlating with the results of previous work on the effect of IFN on viral replication. Strikingly, the inhibition of ASFV replication was linked to the recruitment of MxA protein to perinuclear viral assembly sites...

Dynamin-like MxA GTPase: Structural Insights into Oligomerization and Implications for Antiviral Activity*

Haller, Otto; Gao, Song; von der Malsburg, Alexander; Daumke, Oliver; Kochs, Georg
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.76%
The interferon-inducible MxA GTPase is a key mediator of cell-autonomous innate immunity against a broad range of viruses such as influenza and bunyaviruses. MxA shares a similar domain structure with the dynamin superfamily of mechanochemical enzymes, including an N-terminal GTPase domain, a central middle domain, and a C-terminal GTPase effector domain. Recently, crystal structures of a GTPase domain dimer of dynamin 1 and of the oligomerized stalk of MxA (built by the middle and GTPase effector domains) were determined. These data provide exciting insights into the architecture and antiviral function of the MxA oligomer. Moreover, the structural knowledge paves the way for the development of novel antiviral drugs against influenza and other highly pathogenic viruses.

Hepatitis B virus core protein with hot-spot mutations inhibit MxA gene transcription but has no effect on inhibition of virus replication by interferon α

Zhijian, Yu; Zhen, Huang; Fan, Zhang; Jin, Yang; Qiwen, Deng; Zhongming, Zeng
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 20/10/2010 EN
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27.98%
It has been reported that hepatitis B virus (HBV) core protein (HBc) can inhibit the transcription of human interferon-induced MxA gene. In this study, we investigated whether HBc protein mutations at hot spots (L60V, S87G and I97L) could still inhibit MxA transcription and the potential significance of this inhibition in virus replication in vitro. Our data indicated that the IFN-induced MxA mRNA expression level and MxA promoter activity was significantly down-regulated by mutant protein of HBc(I97L), compared to WT and the other two mutated HBc proteins(L60V or S87G). However, in Huh7 cells stably expressing WT or the mutated HBc proteins (L60V, S87G or I97L), IFN-α could inhibit the extra- and intracellular HBV DNA level and HBsAg secretion to a similar level compared to that in cells transfected with control plasmids. In conclusion, HBc protein with I97L mutation may play an especial role in suppressing the transcription of MxA gene. Moreover, the inhibitory effect on MxA gene transcription by the WT or mutated HBc proteins (L60V, S87G and I97L) has no impact on inhibition of HBV replication by IFN-α in Huh7 cells. The clinical significance of the inhibitory effect of MxA gene transcription by HBc protein requires further study.

Structure of the MxA stalk elucidates the assembly of ring-like units of an antiviral module

Daumke, Oliver; Gao, Song; von der Malsburg, Alexander; Haller, Otto; Kochs, Georg
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
27.85%
The dynamin-like MxA GTP ase (Myxovirus resistance protein 1) mediates cellular resistance against a wide range of viruses. MxA is composed of an amino-terminal G domain, a middle domain and a carboxy-terminal GTPase effector domain. We recently determined the structure of the middle domain and GTPase effector domain of MxA constituting an elongated helical stalk, and elucidated the mechanism how the stalk mediates formation of ring-like MxA oligomers. Here, we shortly review our work and discuss the MxA rings as functional units of a cellular module orchestrating and executing the antiviral response.

MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: Association with muscle involvement

O’Connor, Kevin A.; Abbott, Kathy A.; Sabin, Brad; Kuroda, Maxine; Pachman, Lauren M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.76%
Juvenile dermatomyositis (JDM), a systemic vasculopathy, is characterized by inflammation of skin and muscle. Muscle biopsies from untreated JDM patients show upregulation of type I interferon (IFN)-inducible genes, including myxovirus resistance protein A (MxA). The present study examines whether MxA mRNA expression in peripheral blood mononuclear cells (PBMC) from JDM patients: (1) is elevated compared to healthy controls, (2) reflects disease activity, and (3) changes with the onset of clinically effective treatment. MxA mRNA expression in JDM PBMC obtained at the initial clinic visit was elevated compared to controls and was positively correlated with Disease Activity Score (DAS) for muscle, but not with DAS for skin, suggesting that damage to skin and muscle in JDM may each have a discrete pathophysiology. During the course of clinically effective treatment, decrease in muscle symptoms was associated with a decrease in PBMC MxA mRNA expression.

Interferon-induced Antiviral Protein MxA Interacts with the Cellular RNA Helicases UAP56 and URH49*

Wisskirchen, Christian; Ludersdorfer, Thomas H.; Müller, Dominik A.; Moritz, Eva; Pavlovic, Jovan
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.85%
Mx proteins are a family of large GTPases that are induced exclusively by interferon-α/β and have a broad antiviral activity against several viruses, including influenza A virus (IAV). Although the antiviral activities of mouse Mx1 and human MxA have been studied extensively, the molecular mechanism of action remains largely unsolved. Because no direct interaction between Mx proteins and IAV proteins or RNA had been demonstrated so far, we addressed the question of whether Mx protein would interact with cellular proteins required for efficient replication of IAV. Immunoprecipitation of MxA revealed its association with two closely related RNA helicases, UAP56 and URH49. UAP56 and its paralog URH49 play an important role in IAV replication and are involved in nuclear export of IAV mRNAs and prevention of dsRNA accumulation in infected cells. In vitro binding assays with purified recombinant proteins revealed that MxA formed a direct complex with the RNA helicases. In addition, recombinant mouse Mx1 was also able to bind to UAP56 or URH49. Furthermore, the complex formation between cytoplasmic MxA and UAP56 or URH49 occurred in the perinuclear region, whereas nuclear Mx1 interacted with UAP56 or URH49 in distinct dots in the nucleus. Taken together...

Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA

Mitchell, Patrick S.; Patzina, Corinna; Emerman, Michael; Haller, Otto; Malik, Harmit S.; Kochs, Georg
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 18/10/2012 EN
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27.92%
MxA is an interferon-induced dynamin-like GTPase with wide-ranging antiviral activity, which hinges upon detection of unique viral structures that differ across virus families. Despite elucidation of its structure, the basis of MxA antiviral specificity remains enigmatic. We used an evolution-guided approach to identify the loop L4 of MxA as a hotspot for recurrent positive selection in primates. Further, we show that single amino acid changes in L4 are necessary and sufficient to explain dramatic differences in species-specific antiviral activity of primate MxA proteins against the orthomyxoviruses Thogoto virus and influenza A virus. Taken together, our findings identify a genetic determinant of MxA target recognition and suggest a model by which MxA achieves antiviral breadth without compromising viral specificity.

Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein

Mänz, Benjamin; Dornfeld, Dominik; Götz, Veronika; Zell, Roland; Zimmermann, Petra; Haller, Otto; Kochs, Georg; Schwemmle, Martin
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.98%
The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.

An evolutionary perspective on the broad antiviral specificity of MxA

Mitchell, Patrick S.; Emerman, Michael; Malik, Harmit S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.44%
Germ line encoded antiviral defenses in vertebrate cells tend to be either broadly acting factors that exploit general features of viral replication or effectors with strong pathogen preference by virtue of specific recognition of viral proteins. The Mx GTPases, however, are atypical since they have broad antiviral activity against a wide range of RNA and DNA viruses despite specifically targeting different proteins across virus families. This review presents recent advances in understanding the biochemical properties and evolution of the primate ortholog MxA, and discusses how this information begins to provide molecular insights into the mechanisms behind the intriguing conundrum of how MxA is able to engage a diversity of viral proteins yet elicit antiviral breadth.

The Human Interferon-Induced MxA Protein Inhibits Early Stages of Influenza A Virus Infection by Retaining the Incoming Viral Genome in the Cytoplasm

Xiao, Han; Killip, Marian J.; Staeheli, Peter; Randall, Richard E.; Jackson, David
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /12/2013 EN
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27.44%
The induction of an interferon-induced antiviral state is a powerful cellular response against viral infection that limits viral spread. Here, we show that a preexisting antiviral state inhibits the replication of influenza A viruses in human A549 cells by preventing transport of the viral genome to the nucleus and that the interferon-induced MxA protein is necessary but not sufficient for this process. This represents a previously unreported antiviral function of MxA against influenza A virus infection.

MxA mRNA Quantification and Disability Progression in Interferon Beta-Treated Multiple Sclerosis Patients

Serana, Federico; Imberti, Luisa; Amato, Maria Pia; Comi, Giancarlo; Gasperini, Claudio; Ghezzi, Angelo; Martinelli, Vittorio; Provinciali, Leandro; Rottoli, Maria Rosa; Sotgiu, Stefano; Stecchi, Sergio; Vecchio, Michele; Zaffaroni, Mauro; Cordioli, Cinzi
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 14/04/2014 EN
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27.98%
Even though anti-interferon beta (IFNβ) antibodies are the main determinants of IFNβ bioactivity loss and Myxovirus-resistance protein A (MxA) is the most established marker of IFNβ biological activity in IFNβ-treated multiple sclerosis patients, their usefulness in the routine clinical practice is still debated. Therefore, 118 multiple sclerosis patients naïve for treatment were enrolled for a 3-year longitudinal observational study mimicking the conditions of a real-world setting. In order to evaluate the kinetics of bioactivity loss in blood samples obtained every 6 months after therapy initiation, MxA and interferon receptor isoform/subunit mRNA were quantified by real-time PCR, anti-IFNβ binding antibodies were detected by radioimmunoprecipitation, and neutralizing antibodies by cytopathic effect inhibition assay. Clinical measures of disease activity and disability progression were also obtained at all time points. We found that, at the individual-patient level, the response to IFNβ therapy was extremely heterogeneous, including patients with stable or transitory, early or late loss of IFNβ bioactivity, and patients with samples lacking MxA mRNA induction in spite of absence of antibodies. No interferon receptor isoform alterations that could explain these findings were found. At the group level...