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• W2971569674 abstract "The incidence of progressive multifocal leukoencephalopathy (PML) among patients living with HIV (PML-HIV) decreased in the antiretroviral therapy (ART) era [1]. JC virus (JCV) infection of the brain remains a devastating disease [2]. Given the lack of drugs controlling JCV, initiation of ART and subsequent recovery of JCV-specific CD4+ and CD8+ T-cell immune responses remain the only therapeutic option. Although the 1-year survival rate increased from 10% to 50%, other strategies are required [3]. IL-7 is a cytokine regulating peripheral T-cell survival and homeostasis. High circulating and tissular levels of IL-7 reached after administration of the recombinant human cytokine in lymphopenic patients promotes immune reconstitution by increasing mainly homeostatic expansion of peripheral CD127+ CD4+ and CD8+ T-cell populations, but also antigen-specific T-cell responses [4,5]. Here, we report the control of PML by recombinant human IL-7 (rhIL-7) as a single intervention in an HIV-1-infected patient developing PML despite an already controlled HIV-1 infection on ART. A 49-year-old white woman presented on January 2016 with seizures, hemiparesis and confusion. She was known for HIV-1 infection since 1989 with a CD4+ T-cell nadir of 337/μl (11%), and HIV-associated neurocognitive disorders in 2013 successfully controlled by abacavir, lamivudine and maraviroc and boosted-darunavir. Her plasmatic HIV load was undetectable since 2014, and her blood CD4+ T-cell count was more than 400/μl (>20%) since 2006. Brain MRI revealed asymmetric T1-hypointense and T2-hyperintense white matter lesions (Fig. 1a and b). Cerebrospinal fluid JCV load was of 5000 copies/ml (Fig. 1c). Plasmatic HIV viral load was undetectable and her blood CD4+ and CD8+ T-cell count were, respectively, of 711 (34%) and 1156/μl (56%). As her HIV infection was already controlled, ART intensification would have been meaningless. We therefore decided to initiate rhIL-7 in February 2016, with 4 weekly intramuscular injections of 10 μg/kg. Repeated CSF analysis following rhIL-7 treatment showed undetectable JC viral load. Blood CD4+ and CD8+ T-cell count peaked after the 4th rhIL-7 administration to 1789 (39%) and 2524/μl (55%). IFNγ Elispot with a pool of JCV-specific peptides became positive following rhIL-7 treatment, indicating functional recovery of specific anti-JCV memory T-cell responses [6]. Clinical status improved gradually with recovery of the motor dysfunction and normal alertness in April 2016. Repeated brain MRI showed global stabilization of PML lesions. On August 2017, 18 months after the last rhIL-7 injection, repeated CSF analysis showed undetectable JC viral load, while blood CD4+ and CD8+ T-cell counts remained higher than baseline levels. Brain MRI showed PML sequalae with brain atrophy. No side effects related to rhIL-7 was observed and, in particular, no immune reconstitution inflammatory syndrome (IRIS).Fig. 1: Brain MRI, JC virus virological monitoring and T-cell counts over time.(a and b) Brain MRI at diagnosis on January 2016, axial sections. (a) T1-weighted sequencing. (b) Fluid-attenuated inversion recovery sequencing. (c) Time course of the JC viral load in cerebrospinal fluid and CD4+ and CD8+ T-cell count in blood. Left axis: CD4+ (solid shapes) and CD8+ (empty shapes) T-cell count in blood (/μl). Right axis: cerebrospinal fluid JC viral load (copies/ml).Several approaches have been recently proposed for promoting virus-specific immune responses in PML patients. Infusion of ex-vivo expanded allogeneic human leukocyte antigen-matched T cells specific for BK virus, another polyomavirus sharing homology with JCV, was shown to be associated with decrease in JCV replication, development of PML-IRIS and PML stabilization in three patients [7]. This promising strategy appears technically challenging and not readily accessible in clinical practice. The immune checkpoint inhibitors targeting the inhibitory T-cell surface receptor programmed cell death protein-1 (PD-1) were used in PML patients with various underlying conditions, including two PML-HIV [8–10]. Blockade of PD-1 may have unleashed antiviral T cells to control JCV replication, and led to PML stabilization or improvement in eight out of 10 patients. Immune checkpoint blockade may represent a readily accessible immunotherapy for PML, although their safety profile have to be considered, as immune-related adverse events requiring immunosuppressive drugs might hamper the ultimate control of PML. Although never reported in PML-HIV, rhIL-7 associated with ART may be of interest. IL-7 has been shown to promote anti-JCV immune responses in PML patients with idiopathic CD4+ T-cell lymphocytopenia and hematological malignancies [11–16]. In the patient described here, HIV infection was already controlled by ART and PML occurred as a plausible consequence of persistent functional immune defects despite a sustained virological suppression and a satisfying quantitative immune recovery. Initiation of rhIL-7 was followed by a long-standing increase in circulating CD4+ and CD8+ T cells, recovery of IFNγ production by JCV-specific T cells, in-vivo control of JCV replication and finally stabilization of PML. As rhIL-7 was the single intervention we made, the observed immunological benefit leading to PML control was probably directly related to rhIL-7 effect. Because isolated case reports bias the literature by over-reporting positive results [17], further prospective studies aiming to delineate the efficiency and the respective position of these new therapeutic strategies are imperative. Acknowledgements We thank Revimmune for providing recombinant human IL-7 under a French Temporary Authorization for Use procedure. M.G. and G.M.-B. wrote the article; F.B. interpreted brain MRI; C.M. performed virological analysis; Y.T. performed IFNγ Elispot; P.D., S.R. and G.M.-B. managed the patient. All authors contributed to article reviewing. Conflicts of interest There are no conflicts of interest." @default.
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• W2971569674 date "2019-10-01" @default.
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• W2971569674 title "IL-7 immunotherapy for progressive multifocal leukoencephalopathy in a patient with already controlled HIV-1 infection on antiretroviral therapy" @default.
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