The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial

The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01(B) vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01(B)_2 group, N=64) or 3 (F4/AS01(B)_3 group, N=62) doses of F4/AS01(B) or placebo (control group, N=64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4(+) T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01(B)_2 and control group (0.073 log(10)copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01(B)_3 and control group (-0.096 log(10)copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4(+) T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01(B) recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01(B)_2 group: angioedema). F4/AS01(B) induced polyfunctional F4-specific CD4(+) T-cells, but had no significant impact on F4-specific CD8(+) T-cell and anti-F4 antibody levels.F4/AS01(B) had a clinically acceptable safety profile, induced F4-specific CD4(+) T-cell responses, but did not reduce HIV-1 VL, impact CD4(+) T-cells count, delay ART initiation, or prevent HIV-1 related clinical events

Altered Thymic Function during Interferon Therapy in HCV-Infected Patients

Interferon alpha (IFNα) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFNα therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFNα therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naïve T-cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFNα therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFNα-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFNα therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFNα-treated patients

Immunoregulatory molecule expression on extracellular microvesicles in people living with HIV

IntroductionPeople living with HIV (PLWH) now benefit from combined antiviral treatments that durably control viral replication. These antiretroviral treatments decrease mortality and improve quality of life in PLWH, but do not completely control the excessive non-specific activation of the immune system in PLWH. This chronic immune activation is a key element of HIV immunopathology that contributes to the pathophysiology of inflammatory comorbid conditions, such as cardiovascular disorders, cancer and autoimmune diseases. Circulating non-exosomal extracellular vesicles, also known as microparticles (MPs) are detected in these diseases and have been linked to immune activation. The objective of this study was to characterize the MPs present in PLWH and to assess their association with chronic immune activation.MethodsWe performed flow cytometry for the complete phenotypic characterization of MPs from fresh plasma from PLWH and from people without HIV as the control group. The absolute number, size and cellular origin of MPs were evaluated. The immunoregulatory profile was determined by cell origin, for MPs derived from platelets (PMPs), monocytes (MMPs) and T lymphocytes (LMPs).ResultsPLWH had significantly more circulating MPs than controls, for MPs of all sizes originating from T lymphocytes, red blood cells, neutrophils, dendritic cells, B lymphocytes and endothelial cells. PMPs and MMPs were not more numerous in PLWH, but the immunoregulatory phenotypes of these MPs differed between PLWH and controls. These differences in immunoregulatory molecule expression profile were also observed for LMPs. PDL1, ICOSL, CCR5, TGFβ1, MHC classes I and II, TRAIL, CXCR4, OX40, DC-SIGN, CTLA4 and PDL2 were more strongly expressed on the surface of MPs from PLWH than on those from controls.ConclusionMPs are an important element in intercellular communication, making it possible to transfer phenotypes and functions to immune cells. The significantly higher numbers of MPs expressing diverse immunomodulatory molecules in PLWH may make a major contribution to the maintenance and/or the development of immune-cell activation in these individuals

Mort lymphocytaire et infection par le VIH (elations avec, l'état d'activation cellulaire, la réplication virale, les chimiokines et leurs récepteurs, la molécule Fas)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Etude des rôles des voies Notch et du couple IL-7 / IL-7R au cours des étapes précoces de la différenciation lymphoïde T chez l'Homme

Nous avons au cours de notre travail de thèse tenté de préciser les outils nécessaires àamplifier le potentiel lymphocytaire T de précurseurs hématopoïétiques chez l Homme. Aucours de la différenciation lymphoïde T deux facteurs semblent importants, Notch et l IL7.Nous avons étudié le rôle de l IL7 et de Notch au cours de la différenciation T humaine. Nousavons montré que seule l IL7 est indispensable à la différenciation des thymocytes immatureshumains. L activation de la voie Notch potentialise la survie et la prolifération induite parl IL7 des CD34+TN et des CD4 ISP. Notch maintien l expression de la chaîne a de l IL7Rmalgré la présence de l IL7. Une étude épigénétique a montré que Notch est capable d induirela déméthylation du promoteur de l IL-7Ra permettant son expression.Les résultats obtenus avec les cellules CD34+ de sang de cordon ont montré que Notch etnon l IL7 était indispensable à la différenciation au moins dans les stades précoces. Lesdifférences entre les thymocytes et les CD34+ de sang de cordon ne semblent pas êtreexpliquées par une expression différente des récepteurs Notch. Le système de différenciationdes cellules CD34+ de sang de cordon permet aussi d augmenter le potentiel T in vitro.Nos données confirment le rôle indispensable de Notch et de l IL7 dans la différenciationT avec toutefois des implications différentes selon l origine des précurseurs et du stade dedifférenciation. La poursuite de l étude du rôle de ces deux signaux au cours de l ontogénie Thumaine permettrait de définir les conditions de culture optimale à l amplification dupotentiel T des précurseurs CD34+ dans une optique d utilisation en thérapeutique humaineIn this work, we have attempted to define tools for amplifying the T lymphocyte potentialof hematopoietic precursor cells in man. Notch and IL7 are important factors for Tlymphocyte differentiation. We have studied the roles of IL7 and Notch during human T celldifferentiation. We have shown that only IL7 is essential for differentiation of humanimmature thymocytes. Notch pathway activation potentiates IL7 induced CD34+ TN and CD4ISP survival and proliferation. Notch maintains IL7Ra chain expression in spite of thepresence of IL7. Epigenetic study showed that Notch is able to induce IL7Ra promoterdemethylationOur results on cord blood CD34+ cells showed that Notch, but not IL7, was essential fordifferentiation, at least in early stages. Differences between thymocytes and cord blood cellsCD34+ cells do not seem to be accounted for by different Notch receptor expression. Inaddition, cord blood CD34+ cell differentiation system increases in vitro T lymphocytepotential.Our data confirm the essential role of Notch and IL7 in T cell differentiation, with somediffferences between these two factors according to precursor origin and differentiation stage.Continuation of this study on the role of these signals in human T cell ontogeny would help indefining optimal culture conditions fot T lymphocyte potential amplification from CD34+precursors, in the perspective of therapeutical use in manPARIS-EST-Université (770839901) / SudocPARIS12-Bib. électronique (940280011) / SudocSudocFranceF

Bare Lymphocyte Syndrome chez l adulte. A propos de 2 cas (Description clinique et caractérisation des populations lymphocytaires périphériques)

Le Bare Lymphocyte Syndrome est un déficit immunitaire combiné primitif rare caractérisé par un défaut d expression des molécules du CMH II à la surface des cellules épithéliales thymiques et des cellules présentatrices d antigène conduisant à une lymphopénie chronique CD4 périphérique. Cette pathologie est associée à un pronostic péjoratif en l absence d allogreffe de moelle. Nous avons analysé les caractéristiques cliniques et immunologiques des 2 seuls patients connus à ce jour ayant atteint l âge adulte sans greffe. Les données cliniques et immunologiques standards sont superposables à celles décrites dans la littérature et font discuter l indication systématique de la greffe surtout en l absence de donneur compatible. Des analyses immunologiques approfondies mettent en évidence chez ces patients une dysfonction thymique, une différentiation poussée des populations lymphocytaires T périphériques ainsi qu un état d activation du système immunitaire associé à un vieillissement accéléré notamment osseux. Les similitudes avec d autres pathologies associées à une lymphopénie chronique CD4 comme l infection VIH et la lymphopénie CD4 idiopathique pour lesquelles ont été montré les mêmes phénomènes d activation et de vieillissement souligne de potentiels mécanismes physiopathologiques communs. L importance de la déplétion digestive en lymphocytes T CD4 et ainsi de la translocation microbienne conduisant à l activation immunitaire chez les patients VIH+ et ceux souffrant de lymphopénie idiopathique conduira à l étude immunologique de la muqueuse digestive de nos patients et à la recherche d arguments pour une translocation afin de possiblement mettre en évidence un mécanisme commun à ces pathologiesBare Lymphocyte Syndrome is a rare primary combined immune deficiency characterized by the absence of HLA class II expression on thymic epithelium and antigen presenting cells which leads to a CD4 T cells lymphopenia. This disease is associated with a poor prognosis without heterologous bone marrow transplantation (BMT). We analyzed clinical and immunological parameters of 2 adults who survived without BMT. Clinical and standard immunological data are concordant with literature and lead us to discuss systematic BMT especially if mismatched. Immunological studies of our patients compared with HIV+ and idiopathic CD4 lymphopenia show similar finding like immune activation and accelerated ageing. These results lead us to hypothesize common underlying pathological mechanisms and in particular microbial translocation favored by MALT (Mucosa Associated Lymphoid Tissue) CD4 defect. Further studies concerning gut will be conducted in those 2 patients to confirm this hypothesis.PARIS12-CRETEIL BU Médecine (940282101) / SudocSudocFranceF

Arachnoïdite tuberculeuse spinale (A propos d'un cas et revue de la littérature)

L'arachnoïdite est une complication rare et difficilement prévisible de la méningite tuberculeuse. Nous rapportons ici le cas d'un patient pakistanais pris en charge à l'hôpital Bichat en décembre 1999 pour méningite tuberculeuse. Celle-ci, malgré un traitement anti-tuberculeux bien conduit, s'est rapidement compliquée d'une arachnoïdite spinale. Des injections intrathécales de corticoïdes ont été réalisées mais n'ont pas permis de prévenir l'apparition ultérieure de signe neurologiques. Une revue de la littérature nous a permis de retrouver 23 cas détaillés (contexte de survenue, traitement, évolution) d'arachnoïdite spinale tuberculeuse. A partir de ces cas et de notre propre observation nous décrivons dans notre travail les principales caractéristiques cliniques et épidémiologiques de cette affection. Nous détaillons également ses modalités thérapeutiques en rapportant des essais effectués chez l'homme mais également des données issues de modèles animaux. Enfin nous envisageons à partir d'explorations effectuées chez notre patient, dosage des cytokines intrathécales, les bases de son éventuel dépistage précoce.PARIS7-Villemin (751102101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood

International audienceHIV controllers (HIC) maintain control of HIV replication without combined antiretroviral treatment (cART). The mechanisms leading to virus control are not fully known. We used gene expression and cellular analyses to compare HIC and HIV-1-infected individuals under cART. In the blood, HIC are characterized by a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T cell activation gene expression. This balance that persists after stimulation of cells with HIV antigens was consistent with functional analyses showing a bias toward a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. Taking advantage of the characterization of HIC based upon their CD8+ T lymphocyte capacity to suppress HIV-infection, we show here that unsupervised analysis of differentially expressed genes fits clearly with this cytotoxic activity, allowing the characterization of a specific signature of HIC. These results reveal significant features of HIC making the bridge between cellular function, gene signatures, and the regulation of inflammation and killing capacity of HIV-specific CD8+ T cells. Moreover, these genetic profiles are consistent through analyses performed from blood to peripheral blood mononuclear cells and T cells. HIC maintain strong HIV-specific immune responses with low levels of inflammation. Our findings may pave the way for new immunotherapeutic approaches leading to strong HIV-1-specific immune responses while minimizing inflammation.IMPORTANCE A small minority of HIV-infected patients, called HIV controllers (HIC), maintains spontaneous control of HIV replication. It is therefore important to identify mechanisms that contribute to the control of HIV replication that may have implications for vaccine design. We observed a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T-cell activation gene expression in the blood of HIC compared to patients under combined antiretroviral treatment. This profile persists following in vitro stimulation of peripheral blood mononuclear cells with HIV antigens, and was consistent with functional analyses showing a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. These results reveal significant features of HIC that maintain strong HIV-specific immune responses with low levels of inflammation. These findings define the immune status of HIC that is probably associated with the control of viral load