Trials of antivirals in the treatment of multiple sclerosis

Lycke, Jan

doi:10.1111/ane.12839

Cited by 25 publications

(17 citation statements)

References 26 publications

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“…The use of antiviral compounds was encouraged, in part, by their effectiveness in treating AIDS/HIV, the association of HERVs with MS [61], and anti-EBV effects including inhibition of EBV DNA replication. Famciclovir and acyclovir are effective in treating herpes zoster, shingles, chickenpox, and genital herpes, but have not been evaluated as a treatment for MS or failed in a placebo-controlled study in RRMS [62]. Antiherpesviral nucleoside analogs (acyclovir, penciclovir, and ganciclovir) have also received attention.…”

Section: Antiviral Compoundsmentioning

confidence: 99%

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Bar‐Or

Pender

Khanna

et al. 2020

Trends in Molecular Medicine

199

149

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New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention. HighlightsClinical studies show that depletion of B cells reduces disease burden in both relapsing-remitting and progressive multiple sclerosis (MS) patients.

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Section: Antiviral Compoundsmentioning

confidence: 99%

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Bar‐Or

Pender

Khanna

et al. 2020

Trends in Molecular Medicine

199

149

View full text Add to dashboard Cite

show abstract

“…If EBV is the main antigenic stimulus promoting immune-mediated inflammation in MS, it should be possible to treat MS by normalizing the EBV-host balance with antiviral drugs or T-cell therapy. Previous trials with antiherpesvirus drugs in MS did not show any significant improvement in clinical and radiological parameters but highlighted a possible effect in a subgroup with high disease activity (75). Interestingly, a recent study described the case of an HIV-negative patient with relapsing-remitting MS who achieved significant and sustained disease improvement upon treatment with zidovudine/lamivudine (Combivir), a highly active antiretroviral therapy (76).…”

Section: Discussionmentioning

confidence: 98%

Epstein-Barr Virus-Specific CD8 T Cells Selectively Infiltrate the Brain in Multiple Sclerosis and Interact Locally with Virus-Infected Cells: Clue for a Virus-Driven Immunopathological Mechanism

Serafini

Rosicarelli

Veroni

et al. 2019

J Virol

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EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage. To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

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“…Finally, the concept that MS is a rare neurological complication of a very common infection offers the rationale for clinical trials to test the safety and efficacy of antiviral drugs ( 345 , 346 ) and EBV-specific adoptive T cell therapy ( 333 , 334 ) aimed at improving EBV control and restore the EBV-host balance, and for the implementation of a vaccine to reduce the pathogenic potential of EBV ( 347 , 348 ). It is reasonable to foresee that a better knowledge of CD8 T cell-B cell-EBV interactions in MS patients will translate into a new generation of diagnostic and prognostic biomarkers, antiviral therapeutics and preventive interventions for MS.…”

Section: Discussionmentioning

confidence: 99%

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

Veroni

Aloisi

2021

Front. Immunol.

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The cause and the pathogenic mechanisms leading to multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), are still under scrutiny. During the last decade, awareness has increased that multiple genetic and environmental factors act in concert to modulate MS risk. Likewise, the landscape of cells of the adaptive immune system that are believed to play a role in MS immunopathogenesis has expanded by including not only CD4 T helper cells but also cytotoxic CD8 T cells and B cells. Once the key cellular players are identified, the main challenge is to define precisely how they act and interact to induce neuroinflammation and the neurodegenerative cascade in MS. CD8 T cells have been implicated in MS pathogenesis since the 80’s when it was shown that CD8 T cells predominate in MS brain lesions. Interest in the role of CD8 T cells in MS was revived in 2000 and the years thereafter by studies showing that CNS-recruited CD8 T cells are clonally expanded and have a memory effector phenotype indicating in situ antigen-driven reactivation. The association of certain MHC class I alleles with MS genetic risk implicates CD8 T cells in disease pathogenesis. Moreover, experimental studies have highlighted the detrimental effects of CD8 T cell activation on neural cells. While the antigens responsible for T cell recruitment and activation in the CNS remain elusive, the high efficacy of B-cell depleting drugs in MS and a growing number of studies implicate B cells and Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus that is strongly associated with MS, in the activation of pathogenic T cells. This article reviews the results of human studies that have contributed to elucidate the role of CD8 T cells in MS immunopathogenesis, and discusses them in light of current understanding of autoreactivity, B-cell and EBV involvement in MS, and mechanism of action of different MS treatments. Based on the available evidences, an immunopathological model of MS is proposed that entails a persistent EBV infection of CNS-infiltrating B cells as the target of a dysregulated cytotoxic CD8 T cell response causing CNS tissue damage.

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Trials of antivirals in the treatment of multiple sclerosis

Cited by 25 publications

References 26 publications

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

Epstein-Barr Virus-Specific CD8 T Cells Selectively Infiltrate the Brain in Multiple Sclerosis and Interact Locally with Virus-Infected Cells: Clue for a Virus-Driven Immunopathological Mechanism

The CD8 T Cell-Epstein-Barr Virus-B Cell Trialogue: A Central Issue in Multiple Sclerosis Pathogenesis

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