Multiepitopic B- and T-Cell Responses Induced in Humans by a Human Immunodeficiency Virus Type 1 Lipopeptide Vaccine

Gahéry-Segard, Hanne; Pialoux, Gilles; Charmeteau, Bénédicte; Sermet, Sandrine; Poncelet, Hubert; Raux, M.; Tartar, André; Lévy, J. P.; Gras‐Masse, Hélène; Guillet, Jean‐Gérard

doi:10.1128/jvi.74.4.1694-1703.2000

Cited by 136 publications

(87 citation statements)

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“…Lipidated peptides or proteins are promising vaccine candidates for inducing both humoral and cellular immune responses without conventional adjuvants (18)(19)(20). The use of synthetic lipopeptides as vaccines has many advantages, including ease of manufacture, biosafety, and low-cost vaccine development.…”

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confidence: 99%

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Shen

Song

Chen

et al. 2014

The Journal of Immunology

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Cross-presentation is a key function of dendritic cells (DCs), which present exogenous Ags on MHC class I molecules to prime CTL responses. The effects of TLR triggering on the cross-presentation of exogenous Ags by DCs remain unclear. In this study, we used synthetic dipalmitoylated peptides and TLR2 agonist–conjugated peptides as models to elucidate the mechanisms of TLR2-mediated cross-presentation. We observed that the internalization of dipalmitoylated peptides by bone marrow–derived DCs was facilitated by TLR2 via clathrin-mediated endocytosis. The administration of these dipalmitoylated peptide-pulsed bone marrow–derived DCs eliminated established tumors through TLR2 signaling. We further demonstrated that the induction of Ag-specific CTL responses and tumor regression by dipalmitoylated peptides was TAP independent. In addition, presentation of dipalmitoylated peptides by MHC class I molecules was blocked in the presence of an endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO). The endocytosed dipalmitoylated peptide also passed rapidly from early endosome Ag-1–positive endosomes to RAS-related GTP-binding protein 7 (Rab7)–associated late endosomes compared with their nonlipidated counterparts. Furthermore, we found that dipalmitoylated peptide–upregulated Rab7 expression correlated with Ag presentation via the TLR2/MyD88 pathway. Both JNK and ERK signaling pathways are required for upregulation of Rab7. In summary, our data suggest that TLR2-mediated cross-presentation occurs through the upregulation of Rab7 and a TAP-independent pathway that prime CTL responses.

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confidence: 99%

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Shen

Song

Chen

et al. 2014

The Journal of Immunology

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“…After 24 h fresh GM-CSF and IFN-α were added to the DC culture media. The next day, after a total for 48 h in culture, DCs were pulsed with ANRS HIV LIPO5 peptides: gag (17-35; 253-284); pol (325-355); and nef (66-97; 116-145) [24]. Then, DCs were activated with LPS (purified under Good Manufacturing Practice guidelines) for 6 h, harvested and frozen.…”

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Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

et al. 2014

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Eur. J. Immunol. 2014Immunol. . 44: 2802Immunol. -2810 Clinical immunology 2803 IntroductionTo date, no effective therapeutic or prophylactic HIV vaccines are yet available. Recent encouraging results from the RV 144 trial showed a modest but statistically significant 31% reduction in the rate of HIV infection in vaccinated healthy volunteers receiving a prophylactic vaccine [1]. However, immune responses that would eradicate or control HIV are likely to be different from those needed to prevent primary infection. Indeed, eradication of HIV infection is likely to depend on the establishment of strong cytotoxic T lymphocytes, while prevention of infection will likely depend on the establishment of antibodies neutralizing the virus [2,3]. In both cases, CD4 + T helper cells are necessary for the establishment of robust and long-lasting immunity. Several candidate vaccines are under evaluation including peptides, inactivated virus, viral vectors, and ex vivo-generated DCs [4]. The latter represents an approach to optimize the induction of immune responses [5]. To date, only two studies, in which DCs have been loaded with chemically inactivated autologous virus, have reported a decrease in viral load [6,7]. Another approach using DCs transfected with RNA isolated from autologous virus yielded immune responses without control of viral replication [8]. However, these very promising data with inactivated autologous virus still need to be reproduced. For large scale use of DC vaccination, it would be advantageous to identify an antigenic cargo that could be used without having to isolate and expand the autologous virus which necessitates antiretroviral treatment interruption. We report here the safety and immunogenicity of a new DC platform loaded with five HIV-1-derived lipopeptides (LP) [9] in HIV-1-infected patients treated with highly active antiretroviral treatment (HAART). The study design included a 6-month analytical treatment interruption (ATI), a period which allowed us to evaluate the effects of vaccine-elicited immune responses on viral replication (Fig. 1). Results Patients and study outcomesTwenty patients were screened and 19 were enrolled within 17 months. Baseline characteristics of patients are reported in Table 1. All patients received the four vaccinations with no changes in vaccine dose. All patients but one completed the trial at 48 weeks.The vaccination was well tolerated. Two patients reached a safety endpoint (CD4 + T-cell counts below 500 cells/μL) during the vaccination phase while no safety endpoints were observed during the ATI phase. Systemic or local adverse events were mild or moderate (grade 1 or 2) and resolved in less than 2 days in the majority of cases. All patients stopped HAART at 24 weeks post inclusion except two of them who stopped at 25 and 26 weeks.Through 48 weeks, eight patients reached the immunology endpoint defining a failure of the strategy: at 28 (two patients), 32 (three patients), 36, 40, and 44 weeks. Three of these patients resumed HAART. No clinical events or pro...

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“…Par exemple, dans l'essai de phase I, ANRS VAC 04, 28 volontaires sains ont reçu 3 injections de 6 lipopeptides dérivés des protéines Nef, Gag et Env du VIH et la tolérance a été bonne. On a constaté des réponses anticorps chez 90 % des sujets, et chez 80 % des sujets des réponses T CD4 ayant de multiples spécificités, ainsi que de nombreuses réponses T CD8 anti-Gag et anti-Nef de longue durée [24,25]. Dans les protocoles vaccinaux de l'ANRS engagés avec les lipopeptides, d'autres formulations ont été testées, incluant la présence de l'épi-tope auxiliaire de la toxine tétanique, ou un vecteur ALVAC, dérivé du Canari Pox.…”

Section: Les Premiers Essais De Vaccination Réalisés Chez L'homme Aveunclassified

De l’immunologie fondamentale au développement de la vaccinologie

Choppin

2008

Med Sci (Paris)

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Multiepitopic B- and T-Cell Responses Induced in Humans by a Human Immunodeficiency Virus Type 1 Lipopeptide Vaccine

Abstract: ؉ T cells were also obtained. These CD8 ؉ T cells were able to recognize naturally processed viral proteins. Finally, specific gamma interferon-secreting CD8 ؉ T cells were also detected ex vivo.

Cited by 136 publications

References 32 publications

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Molecular Mechanisms of TLR2-Mediated Antigen Cross-Presentation in Dendritic Cells

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

De l’immunologie fondamentale au développement de la vaccinologie

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