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Biomedical subjects

Yves Lévy

Publications and source records attributed to Yves Lévy.

12 recordsLinked to original sources
PubMed2006

Clinical safety of HIV lipopeptides used as vaccines in healthy volunteers and HIV-infected adults.

BACKGROUND: HIV-1 lipopeptides have been developed by the French National Agency for AIDS Research (ANRS) for use as candidate vaccine against HIV since 1994. Between 1996 and 2005, four different lipopeptide constructs were tested alone or in combination with recombinant canarypox HIV vaccines in 10 trials conducted in France. The aim of this study was to review clinical safety of HIV lipopeptides. METHODS: A meta-analysis based on individual subject data examined clinical safety data collected in eight preventive trials and two therapeutic trials enrolling 200 HIV-1-uninfected healthy volunteers and 48 HIV-1-infected patients. RESULTS: Of 248 trial participants, eight (3.2%) did not complete follow-up: seven among the 200 healthy volunteers, and one among the 48 HIV-1 infected patients. During the 354 person-years of follow-up, 860 lipopeptides injections were administered. Local reactions were common. However, in trials where lipopeptides were tested without adjuvant and appropriate diluents, none of the vaccinees experienced severe local response. Systemic reactions were generally mild and transient. No grade 4 reaction was reported; 18 subjects experienced grade 3 systemic events related to the vaccination, mainly asthenia, fever, headache and arthralgia. Multivariate analysis showed that female sex, number of injections and diluent (more reactions in 5% glucose alone than in combination with Tris-HCl buffer) significantly increased systemic reactions related to the vaccination. CONCLUSION: These data demonstrate that reactogenicity and systemic safety of HIV lipopeptides vaccine are acceptable both in healthy volunteers and HIV-infected adults.

AIDS Vaccines↗
PubMed2006

Sustained control of viremia following therapeutic immunization in chronically HIV-1-infected individuals.

OBJECTIVE: Viral rebounds inevitably follow interruption of antiretroviral treatment in HIV-1-infected individuals. The randomized ANRS 093 aimed at investigating whether a therapeutic immunization was effective in containing the long-term viral replication following discontinuation of antiretroviral drugs in patients. METHODS: Seventy HIV-1-infected patients effectively treated with antiretroviral drugs were randomized to continue treatment alone or in combination with four boosts of ALVAC 1433 and HIV-LIPO-6T vaccines followed by three cycles of subcutaneous interleukin-2. The impact of vaccination on viral replication was assessed by interrupting antiretroviral drugs first at week 40 and thereafter during follow-up until week 100. Antiretroviral drugs were re-initiated according to predefined criteria. RESULTS: The median cumulative time (days) off treatment was greater in the vaccine group (177) than in the control group (89) (P = 0.01). The proportion of time (mean, SE) without antivirals per-patient was 42.8% (5.1) and 26.5% (4.2) in the vaccine and control groups, respectively (P = 0.005). Viremia (median log10 copies/ml), 4 weeks following the first, second and third treatment interruption was higher in control patients (4.81, 4.44, 4.53) in comparison with vaccinated patients (4.48, 4.00, 3.66) (P = 0.42, 0.015 and 0.024, respectively). HIV-specific CD4 and CD8 T-cell responses elicited by the therapeutic immunization strongly correlated with the reduction of the time of antiviral therapy (P = 0.0027 and 0.016, respectively). CONCLUSION: Our findings provide evidence that therapeutic immunization significantly impacts on HIV-1 replication. This translated into a decrease of up to 40% in the duration of exposure to antiretroviral drugs over 15 months of patients' follow-up.

AIDS Vaccines↗
PubMed2006

Short exposure to Notch ligand Delta-4 is sufficient to induce T-cell differentiation program and to increase the T cell potential of primary human CD34+ cells.

OBJECTIVE: The Notch pathway plays a key role in cell fate choices and in T-cell development. The goal of our study was to evaluate whether a short in vitro stimulation of the Notch pathway may alter human progenitor cell behavior. METHODS: CD34+ cord blood progenitors were exposed for 4 days to either immobilized Notch ligand Delta-4 or in control conditions. Phenotypic and molecular changes induced by the short stimulation were assessed at day 4. Next, long-term alteration of the fate of these progenitors was assessed in culture conditions suitable for B (coculture with MS5 stromal cells) and T (FTOC and OP9 stromal cells expressing Delta-4 systems) cell differentiation. RESULTS: Notch activation was sufficient to trigger immunophenotypic and molecular changes consistent with early T-cell lineage differentiation. Delta-4 induced, in 4 days, CD7+cytCD3epsilon+ cells. This paralleled at the gene-transcription level with de novo expression of several T cell-related transcription factors and TCRgamma rearrangement, while B cell transcripts were simultaneous silenced. As compared to non-Delta-4 primed cells, these early changes translated to long-term alteration of the potential of cells. Delta-4 priming led to an acceleration of T-cell development, including a completion of the TCR rearrangement, when cells were cultured in systems suitable for T-cell development while B-cell development was inhibited. CONCLUSION: A transient Notch activation is sufficient to promote T-cell differentiation from cord blood CD34+ cells. This system may be a useful tool for the amplification and the quantification of the T potential of CD34+ cells in various disease conditions.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients.

OBJECTIVE: Several lines of evidence suggest that the immune system may control HIV-1 replication, but that it could fail in the long term. Strategies aimed to elicit specific immune responses may enable patients to contain virus replication. METHODS: HIV-1-infected patients were randomized to continue either their antiviral therapy alone (controls; n = 37) or with four boosts of vaccination combining ALVAC-HIV (vCP1433) and Lipo-6T vaccines (weeks 0, 4, 8, 12) followed by three cycles of subcutaneous interleukin-2 (weeks 16, 24, 32) (Vac-IL-2 group; n = 34). RESULTS: Of the Vac-IL-2 group, 15/32 (47%) exhibited a stable HIV p24 antigen-proliferative response compared with 8/33 (24%) controls (P = 0.049). After vaccination, 19/33 (58%) of the Vac-IL-2 group exhibited a multiepitopic HIV-1-specific CD4 cell proliferative response compared with 9/36 (25%) of controls (P = 0.006). The breadth and the magnitude of HIV-specific interferon-gamma-producing CD8 T cells improved in the Vac-IL-2 group. After stopping antiviral drugs, 24% of the Vac-IL-2 group lowered their viral set point compared with 5% of controls (P = 0.027). Logistic-regression analysis demonstrated that vaccine-elicited immunological responses were predictive of virological control (P = 0.046 and 0.014 for stable and multiepitopic CD4 T cell responses, respectively). CONCLUSION: This study provides proof of the concept that therapeutic immunization before antiviral drug cessation may contribute to the containment of HIV replication.

AIDS Vaccines↗
PubMed2005

Therapeutic HIV vaccines: an update.

The goal of therapeutic immunization in HIV infection is to induce strong and sustained immune responses against HIV. Several arguments suggest that the immune system may contain HIV replication in the long term before declining. The potency on new antiviral regimens in clinic has provided an opportunity to improve the control of the virus replication by the immune system. In clinical terms, this might allow patients to delay or to stop antiviral therapy and to minimize the duration of the exposition to antiviral drugs.

AIDS Vaccines↗
PubMed2005

Common variable immunodeficiency: the immune system in chaos.

Common variable immunodeficiency (CVID) is a heterogeneous disorder that is associated with low serum-immunoglobulin concentrations, defective specific-antibody production and an increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts. In spite of the identification of genes that are associated with several known primary immunodeficiencies, the basic immunologic and molecular defects of the majority of patients with CVID have remained obscure. Most of the studies aimed at understanding the immunopathogenesis of CVID suggest that this condition is primarily a T-cell disorder, although renewed attention on the genetic linkage and haplotype analysis in families of patients with CVID and on the role of dendritic cells and B cells has revealed several interesting features. This new information should assist in understanding the pathogenesis of CVID and improving the therapeutic strategies.

B-Lymphocytes↗
PubMed2004

Natural antibodies sustain differentiation and maturation of human dendritic cells.

The differentiation and maturation of dendritic cells (DCs) is governed by various signals in the microenvironment. Monocytes and DCs circulate in peripheral blood, which contains high levels of natural antibodies (NAbs). NAbs are germ-line-encoded and occur in the absence of deliberate immunization or microbial aggression. To assess the importance of NAbs in the milieu on DC development, we examined the status of DCs in patients with X-linked agammaglobulinemia, a disease characterized by paucity of B cells and circulating antibodies. We demonstrate that the in vitro differentiation of DCs is severely impaired in these patients, at least in part because of low levels of circulating NAbs. We identified NAbs reactive with the CD40 molecule as an important component that participates in the development of DCs. CD40-reactive NAbs restored normal phenotypes of DCs in patients. The maturation process induced by CD40-reactive NAbs was accompanied by an increased IL-10 and decreased IL-12 production. The transcription factor analysis revealed distinct signaling pathways operated by CD40-reactive NAbs compared to those by CD40 ligand. These results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.

Adolescent↗
PubMed2004

Common variable immunodeficiency is associated with defective functions of dendritic cells.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and defects in T-cell functions that could be primary or secondary. We addressed whether CVID is associated with impairment in the dendritic cell (DC) compartment, as DCs play a central role in the development of adaptive immunity. We demonstrate that DCs from CVID patients display severely perturbed differentiation, maturation, and function, and express markedly reduced levels of the costimulatory molecules that are critical for T-cell stimulation. Patients' DCs induced weak proliferation of allogeneic T cells and produced significantly low amounts of interleukin-12 (IL-12) upon CD40 signaling. Multiple defects in the immune system, including malfunctioning of DCs, appear to be prominent features of CVID patients. Impairment in both the innate and adaptive compartments of the immune system may thus cumulatively account for the inability of CVID patients to eradicate pathogens through conventional immune pathways, thus resulting in an increased risk for recurrent bacterial infections.

Cell Differentiation↗
PubMed2004

Presence of HIV-specific CD4+ T-cell responses in HIV-infected subjects with sustained virologic control after highly active antiretroviral therapy.

HIV-specific CD4+ T-helper cell responses in 40 subjects with chronic infection (CI) who had virus suppression after highly active antiretroviral therapy (HAART) were compared with those in 34 subjects treated during primary infection (PI). A CD4+ T-cell proliferative response to HIV p24 protein was present in 50% of these subjects compared with 79% of subjects treated during PI. The existence of a proliferative response in CI subjects was associated with a higher CD4+ T-cell count at initiation of HAART, a longer duration of virus suppression, and a higher CD4+ T-cell count at the time of analysis. These results show that an HIV-specific proliferative response is preferentially observed in treated CI subjects with CD4+ T-cell counts of >200/microL. However, in treated CI subjects with a significant degree of CD4+ T-cell depletion (<200/microL), it may also be observed in 35% provided that the duration of virus suppression is long enough, which may have implications for future therapeutic strategies.

Adolescent↗
PubMed2004

High-dose therapy plus autologous hematopoietic stem cell transplantation for human immunodeficiency virus (HIV)-related lymphoma: results and impact on HIV disease.

BACKGROUND AND OBJECTIVES: The aim of this study was to assess the feasibility of high-dose chemotherapy plus autologous hematopoietic stem cell transplantation (HDC/AHSCT) in AIDS-related lymphoma (ARL), and its long-term impact in patients with human immunodeficiency virus (HIV) treated with highly active antiretroviral therapy (HAART). DESIGN AND METHODS: Fourteen patients with relapsed or resistant ARL (8 with nonHodgkin's lymphoma and 6 with Hodgkin's disease) were treated with HDC/AHSCT while on HAART. HIV-1 proviral DNA load was quantified in 11 grafts. RESULTS: Hematologic reconstitution was good. No toxic deaths occurred. Despite the large number of cells harboring HIV-1 proviral DNA (105 to 109) re-infused with the graft, HAART controlled HIV replication and led to CD4 cell reconstitution in 7 of the 8 patients who were still alive six months after AHSCT. Only two patients had opportunistic infections after AHSCT. There were no significant changes in viral load (VL) or CD4+ cell counts in most patients. One month after AHSCT, 10 patients were in complete remission (CR). Seven patients died from lymphoma between 1 and 10 months after AHSCT, and a further two patients died in CR (one from AIDS at 16 months, one from another tumor at 28 months). Five patients are alive: four are in CR, 14, 19, 32 and 49 months after AHSCT (median CD4+ cell count= 445/mL; undetectable VL in 3 patients), and one is being treated for relapsed lymphoma 36 months after AHSCT. INTERPRETATION AND CONCLUSIONS: HDC/AHSCT is feasible in AIDS-related lymphoma, in terms of harvesting, engraftment, adverse events and HIV control. It should be proposed to patients with poor-prognosis chemosensitive lymphoma.

Adult↗
PubMedDate not supplied

[Cytokine therapies in HIV infection].

The theoretical objectives of cytokine therapies in HIV infection are to impact T cell homeostasis and/or to improve immune functions or the mobilization of the HIV reservoir. Among cytokines, IL-2 and IL-7 are promising agents under clinical evaluation. Intermittent administration of IL-2 is by far the furthest studied strategy in HIV infection. This cytokine increases CD4 T lymphocytes in HIV-infected individuals. Recent clinical data showed that this effect is sustained over years. IL-2 therapy induces a peripheral expansion of T cells as a consequence of prolonged survival of T cells and decreased immune activation. These effects suggest that a cytokine therapy may interfere with critical factors of HIV disease. Recent data provide arguments that IL-2 therapy improves immune functions in HIV-infected patients. Whether these effects may be translated into clinical benefits is under evaluation in ongoing phase III studies. The potential interest of IL-7 in the treatment of HIV-infection is based on its crucial role on T cell homeostasis both in thymic output and peripheral T proliferation and survival. Although no data in human are still available, recent studies provide arguments to assess this cytokine in HIV infection. Phase I studies are ongoing or planned.

CD4-Positive T-Lymphocytes↗