Marie-Ghislaine de Goër de Herve

Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy.

Background Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery. Methods and Findings All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008). Conclusions The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death. Trial Registration ClinicalTrials.gov NCT00120367

CD25 Appears Non Essential for Human Peripheral Treg Maintenance In Vivo

Background IL-2 has been reported to be critical for peripheral Treg survival in mouse models. Here, we examined Treg maintenance in a series of paediatric liver transplant recipients who received basiliximab, a therapeutic anti-CD25 monoclonal antibody. Methodology/Principal Findings FoxP3+ CD4 T cells were analyzed by flow cytometry before liver grafting and more than 9 months later. We found that in vivo CD25 blockade did not lead to Treg depletion: the proportion of FoxP3+ cells among CD4 T cells and the level of FoxP3 expression were both unchanged. IL-2Rβ expression was enhanced in FoxP3+ cells both before and after basiliximab treatment, while the level of IL-2Rγ expression was similar in Tregs and non-Tregs. No significant change in the weak or absent expression of IL-7Rα and IL-15Rα expression on FoxP3+ cells was observed. Although the proportion of FoxP3+ cells among CD4 T cells did not vary, food allergies occurred more rapidly after liver grafting in patients who received basiliximab, raising questions as to Treg functionality in vivo in the absence of functional CD25. Conclusions CD25 appears non essential for human Treg peripheral maintenance in vivo. However, our results raise questions as to Treg functionality after therapeutic CD25 targeting.

Immunological Hallmarks of JC Virus Replication in Multiple Sclerosis Patients on Long-Term Natalizumab Therapy

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is the main adverse effect of natalizumab. Detectable JC virus-specific effector memory T-cell (TEM) responses may indicate ongoing JCV replication. We detected JCV-specific TEM responses in blood of patients with multiple sclerosis (MS) treated with natalizumab, including 2 patients with PML. The frequency of detection of these responses increased with the time on natalizumab. Thus, a subset of MS patients exhibit immunological hallmarks of JCV replication during prolonged natalizumab therapy.

Human microglial cells express a functional IL-12 receptor and produce IL-12 following IL-12 stimulation

Microglial cells (MC) are IL‐12 producers in the central nervous system. Here, we found that IL‐12 receptor subunits β1 and β2 were both constitutively expressed, and up‐regulated by IFN‐γ, in human primary MC. IL‐12p70, after binding to its receptor, is internalized into vesicles that qualify as early endosomes as indicated by intracellular colocalization with transferrin. IL‐12 induced tyrosine phosphorylation and nuclear translocation of STAT4. IL‐12 signaling in human MC also involved members of the NFκB family. IL‐12p70 and, more effectively, the combination of IL‐12p70 and IFN‐γ, induced IL‐12p40 mRNA expression and bioactive IL‐12p70 production. Human MC, thus, express a functional IL‐12 receptor and produce bioactive IL‐12 following IL‐12 stimulation.

Direct CD4 Help Provision following Interaction of Memory CD4 and CD8 T Cells with Distinct Antigen-Presenting Dendritic Cells

Accumulating evidence suggests that CD4 help is needed at the memory stage to mount effective secondary CD8 T cell responses. In this paper, we report that memory CD4 T cells can provide efficient help to memory CD8 T cells after interaction of the two lymphocytes with distinct dendritic cells. Provision of help to CD8 T cells required direct cell–cell contact and involved both IL-2 and CD40 ligation, within a CD4–CD8 T cell synapse. Thus, following antigenic interaction with APCs, activated memory CD4 and CD8 T cells appear to separate from their respective APCs before meeting each other for help provision, regardless of their Ag specificity. CD4 help for memory CD8 T cells therefore appears to be conditioned primarily not by Ag specificity but by activation status.

Efficacy of Recombinant Human Interleukin 7 in a Patient With Severe Lymphopenia-Related Progressive Multifocal Leukoencephalopathy

In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

Heterospecific CD4 Help to Rescue CD8 T Cell Killers

Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.

Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy After Prolonged CTLA4 Therapy

Abstract Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy-induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery.