Clinical/Scientific Notes

Ananja Middel, MD* Joop E. Arends, MD, PhD* Steven F.L. van Lelyveld, MD, PhD* Sigrid Otto Rob Schuurman Catharina J.M. Frijns, MD, PhD Kiki Tesselaar, PhD Andy I.M. Hoepelman, MD, PhD


Progressive multifocal leukoencephalopathy (PML) is a rare but generally fatal disease due to JC virus (JCV) reactivation, mainly occurring in immunosuppressed patients.1 Therapeutic options are limited to blocking glial cell infection by mirtazapine or restoring cellmediated immunity to acquire viral control.2 Maraviroc (MVC), a chemokine receptor type 5 (CCR5) blocker, effectively suppresses plasma HIV RNA in HIV-1-infected patients and possible immunologic effects, such as enhancement of CD41 T-cell reconstitution, have been attributed to MVC therapy.3 PML has been described in patients with CD41 T-cell lymphocytopenia, either idiopathic or otherwise induced, as in sarcoidosis.1 Similar to HIV-positive patients, these patients have low CD41 T-cell counts and an activated immune system. This led us to postulate that interfering in the CCR5 pathway via MVC might enhance CD41 T-cell recovery by immunomodulating properties, aiming for immune control of the JCV infection. Here, we describe 3 immunocompromised HIV-negative patients diagnosed with PML who were treated off-label with MVC and showed long-term clinical improvement. Methods. The first patient with PML described presented in October 2009 and was started on off-label treatment with MVC. Because of a positive clinical course, 2 subsequent patients diagnosed with PML were started on off-label treatment with MVC in 2010. Standard protocol approvals, registrations, and patient

All patients were started on MVC 300 mg twice daily. They provided written informed consent for off-label treatment with MVC and agreed to extra blood sampling, which was approved by the local medical ethics committee. Laboratory analyses. At each visit, absolute CD41 T-cell counts were measured and peripheral blood mononuclear cells were isolated. Total cell numbers and markers for activation (CD381/HLA-DR1) and proliferation (Ki-671) were determined in CD31CD41 T cells. For patient 1, JCV-specific CD41 T-cell responses were measured at weeks 2 and 42.2 consents.


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JCV viral load evaluation was performed by realtime PCR amplification assay targeting a wellconserved region of the viral Large-T antigen. Results. Patients 1 and 3 had a history of sarcoidosis. Their performance according to the Karnofsky scale was 50 and 20, respectively, at PML diagnosis. Steroids were withdrawn and MVC and mirtazapine were initiated. Patient 2 was diagnosed with an idiopathic CD41 T-cell lymphocytopenia at PML diagnosis with a Karnofsky score of 50 when MVC was started (table). Patients 1 and 2 showed marked clinical improvement in the first 4 weeks after start of MVC with an increase in Karnofsky scores to 70 and 50, respectively, and near blindness improved to regaining visual acuity in both patients. Patient 3 started to experience progressive improvement of right-sided motor function after 10 weeks of MVC treatment, consistent with improvement of the Karnofsky score from 20 to 50. MVC was welltolerated by all 3 patients. Currently, with a follow-up of 4 and 3 years, respectively, patients 1 and 2 are in stable clinical condition while still on MVC 300 mg twice daily therapy. Patient 3 stopped MVC treatment after 21 months, remaining in a stable clinical condition for another 2 years, but died due to an infection with respiratory syncytial virus. Clinical follow-up.

Immunologic and virologic analysis. Overall, CD41 T-cell counts in all 3 patients increased significantly during follow-up. In patient 3, no immunologic or virologic follow-up was performed. In patients 1 and 2, we observed that both activation (CD381/HLADR1) and proliferation markers (Ki-671) in CD41 T cells declined during the course of follow-up. In patient 1, the JCV-specific CD41 T-cell response was analyzed after stimulation with 4 overlapping JCV-derived VP1 peptide pools, showing a significant CD41 T-cell response at weeks 2 and 42. All 3 patients had detectable JCV DNA in the CSF at the time of PML diagnosis (table). After start of MVC, the viral load in patients 1 and 2 became undetectable (,50 copies/mL) at 2 and 6 months, respectively.

Discussion. We describe 3 patients with PML who achieved clinical remission shortly after starting MVC

July 7, 2015

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Baseline characteristics of the 3 patients Patient 1

Patient 2

Patient 3

Demographics Sex




Age, y




Underlying diseases


Idiopathic CD41 Sarcoidosis lymphocytopenia

Total WBC 3 109/L




Total lymphocyte count 3 109/L




CD41 T-cell count








Viral load JCV CSF, copies/mL




Viral load JCV brain biopsy, copies/mL



5 3 108

Immune status


*These authors contributed equally to this work.

Therapy Immunosuppressive therapy prior to PML diagnosis

with a positive effect on survival in HIV and natalizumab-treated patients.5,6 Finally, transcription of JCV is influenced by transcription factors nuclear factor of activated T-cells 4 (NFAT4) and NF-kB.2,7 Oligodendrocytes express CCR5 and interference with this transduction pathway might lead to reduction in viral replication of the JCV. PML is fatal in most cases, with a 1-year survival of 20% and an even lower survival rate after a longer duration of follow-up. However, our 3 patients had a relatively low viral load in the CSF, were over 50 years of age, and 2 out of 3 had nadir CD41 T-cell counts over 100 cells/mL, factors shown to be associated with better outcome.2 Furthermore, withdrawing steroids in patients 1 and 3 and a natural course of idiopathic lymphocytopenia in patient 2 could have attributed to restoration of the CD41 T-cell counts. These factors could have contributed to the successful outcome of MVC treatment.

Prednisolone 30 mg OD for 7 days 3 months prior to PML diagnosis

Methylprednisolone 1,000 mg OD for 3 days, up until the day of PML diagnosis


Prednisolone 30 mg OD for 4–2 months prior to PML diagnosis Prednisolone 80 mg OD 8 weeks up to PML diagnosis

Abbreviations: JCV 5 JC virus; NA 5 not available; OD 5 once daily; PML 5 progressive multifocal leukoencephalopathy; WBC 5 white blood cell count.

for at least 3 years. Furthermore, cellular immunity increased during treatment with MVC, illustrated by improved CD41 T-cell counts in all patients and presence of JCV-specific T-cell responses at weeks 2 and 48 in the patient analyzed. It remains uncertain whether MVC contributes to restoration of cellular immunity or negatively influences JCV viral replication. The exact mechanisms that underlie the potential immunomodulatory and therapeutic effects of CCR5 receptor antagonism in PML are yet to be elucidated. Based on our clinical observations, possible working mechanisms of MVC in PML can be divided into influencing the immune system vs a direct effect on JCV. We hypothesize that MVC positively influences CD41 T-cell reconstitution by downregulating T-cell activation, resulting in less interleukin-2 production.4 In contrast, MVC could directly dampen the inflammatory process by blocking the CCR5 receptor, subsequently diminishing influx of lymphocytes and macrophages at the site of infection. MVC might work as a mediating double-edged sword, where sufficient cellular immunity is crucial in viral control over the JCV but overwhelming and destructive immune response is hampered. In case of IRIS, MVC was shown to reduce the immune response

From University Medical Center Utrecht (A.M., J.E.A., S.F.L.v.L., S.O., R.S., C.J.M.F., K.T., A.I.M.H.); University Medical Center Groningen (A.M.); and Kennemer Gasthuis (S.F.L.v.L.), Haarlem, the Netherlands. Author contributions: A.M. performed medical chart research, performed laboratory experiments, analyzed the data, and wrote the manuscript. J.E.A. contributed to interpretation of the data and writing of the manuscript. S.F.L.L. performed laboratory experiments and contributed to interpretation of the data and writing of the manuscript. S.O. and R.S. performed laboratory experiments and contributed to interpretation of the data. C.J.M.F. contributed to writing of the manuscript. K.T. and A.I.M.H. were responsible for overall supervision on interpretation of the data and writing the manuscript. Study funding: No targeted funding reported. Disclosure: A. Middel reports no disclosures relevant to the manuscript. J. Arends received financial support for consultancy from Abbvie, Janssen-Cilag, MSD, Gilead, BMS, and ViiV healthcare outside the submitted work. S. van Lelyveld has received financial support for research, travel, speaking engagements, or consultancy from BMS, GSK, Janssen-Cilag, Pfizer, Roche, and ViiV healthcare outside the submitted work. S. Otto, R. Schuurman, C. Frijns, and K. Tesselaar report no disclosures relevant to the manuscript. A. Hoepelman has received grant support from Pfizer outside the submitted work. Go to for full disclosures. Received November 7, 2014. Accepted in final form March 12, 2015. Correspondence to Dr. Arends: [email protected] © 2015 American Academy of Neurology 1.



Gheuens S, Wuthrich C, Koralnik IJ. Progressive multifocal leukoencephalopathy: why gray and white matter. Annu Rev Pathol 2013;8:189–215. Gheuens S, Bord E, Kesari S, et al. Role of CD41 and CD81 T-cell responses against JC virus in the outcome of patients with progressive multifocal leukoencephalopathy (PML) and PML with immune reconstitution inflammatory syndrome. J Virol 2011;85:7256–7263. Ahuja SK, Kulkarni H, Catano G, et al. CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nat Med 2008;14:413–420.

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Camargo JF, Quinones MP, Mummidi S, et al. CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation. J Immunol 2009;182:1550–6606. Giacomini PS, Rozenberg A, Metz I, Araujo D, Arbour N, Bar-Or A. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014;370:486–488.



Stefoski D. Fifteen non-fatal outcomes in natalizumabassociated PML/IRIS: the effects of early diagnosis and evolving novel therapies. Presented at the 2014 Joint ACTRIMSECTRIMS meeting, Boston, MA, September 10–13, 2014. Wollebo HS, Melis S, Khalili K, Safak M, White MK. Cooperative roles of NF-kappaB and NFAT4 in polyomavirus JC regulation at the KB control element. Virology 2012;432:146–154.

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Neurology 85

July 7, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Clinical and immunologic effects of maraviroc in progressive multifocal leukoencephalopathy.

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