Lipopeptides induce cell-mediated anti-HIV immune responses in seronegative volunteers

Pialoux, Gilles; Gahéry-Segard, Hanne; Sermet, Sandrine; Poncelet, Hubert; Fournier, Sandra; Gérard, Laurence; Tartar, André; Gras-Masse, Hélène; Lévy, J. P.; Guillet, J G

doi:10.1097/00002030-200107060-00005

Cited by 76 publications

(59 citation statements)

References 26 publications

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“…Proteasomal degradation of large peptide Ova(239-281) and of the ovalbumin protein gave the same precursors of the immunodominant epitope Ova(259-267) (2,3,26). We also observed that large Nef peptides (residues 66 to 97 and 117 to 145), which are rich in HLA binding motifs and well cleaved by proteasomes, may be generated in vaccinated individuals' T-cell responses directed to the predicted epitopes (6,11,29). Here, we showed that complete degradation by T1 cell extract enriched in proteasomes containing LMP-2 and LMP-7 subunits occurs in 8 h for p17(68-93) versus Ͼ72 h for RT(468-495).…”

Section: Degradation Of Large Peptides P17(68-93) and Rt(468-495)mentioning

confidence: 53%

Study of Antigen-Processing Steps Reveals Preferences Explaining Differential Biological Outcomes of Two HLA-A2-Restricted Immunodominant Epitopes from Human Immunodeficiency Virus Type 1

Cohen

Bianco

Connan

et al. 2002

J Virol

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Cytotoxic T-lymphocyte (CTL) responses directed to different human immunodeficiency virus (HIV) epitopesvary in their protective efficacy. In particular, HIV-infected cells are much more sensitive to lysis by anti-Gag/ p17(77-85)/HLA-A2 than to that by anti-polymerase/RT(476-484)/HLA-A2 CTL, because of a higher density of p17(77-85) complexes. This report describes multiple processing steps favoring the generation of p17(77-85) complexes: (i) the exact COOH-terminal cleavage of epitopes by cellular proteases occurred faster and more frequently for p17(77-85) than for RT(476-484), and (ii) the binding efficiency of the transporter associated with antigen processing was greater for p17(77-85) precursors than for the RT(476-484) epitope. Surprisingly, these peptides, which differed markedly in their antigenicity, displayed qualitatively and quantitatively similar immunogenicity, suggesting differences in the mechanisms governing these phenomena. Here, we discuss the mechanisms responsible for such differences.The mechanisms of presentation of intracellular antigens by major histocompatibility class I (MHC-I) molecules are well documented, and several of these steps have been described previously (28). First, antigenic proteins are degraded in peptides by different cytosolic complexes, the most highly implicated and frequently described being the proteasome. Second, peptides are translocated by the transporter associated with antigen-processing (TAP) into the endoplasmic reticulum (ER), where they bind newly synthesized empty MHC-I molecules. Third, stable peptide/MHC-I complexes are exported via the Golgi apparatus to the cell surface, where they can be recognized by CD8 ϩ T cells expressing a specific T-cell receptor. However, the steps in antigen processing which determine a dominant T-cell response are still poorly understood. Elucidating the mechanisms that determine the antigenicity of epitopes for MHC-I presentation is critical for defining targets for peptide-designed vaccines or immunotherapies that limit viral spread.In the present work, we investigated the processing of two HLA-A2-restricted epitopes, p17(77-85), from the Gag/p17 matrix protein, and RT(476-484), from the Pol/reverse transcriptase (RT) complex, which are naturally presented by human immunodeficiency virus (HIV)-infected cells (35). Previous studies have shown that p17(77-85)-specific cytotoxic T-lymphocyte (CTL) clones are more efficient than those specific for RT(476-484) in lysing infected target cells, because of a better presentation of p17 epitope (35,38). To understand the molecular basis of the dominance of p17(77-85) over , a detailed analysis of antigen presentation was performed. First, the kinetics and efficiency of the degradation by enriched proteasome fractions of protein fragments encompassing the epitopes were compared. Binding assays of the digestion products to TAP and of the optimal epitopes to HLA-A2 molecules were then performed. The avidities of spontaneously induced CD8 ϩ T cells against each epitope in HIV-infected ...

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Section: Degradation Of Large Peptides P17(68-93) and Rt(468-495)mentioning

confidence: 53%

Study of Antigen-Processing Steps Reveals Preferences Explaining Differential Biological Outcomes of Two HLA-A2-Restricted Immunodominant Epitopes from Human Immunodeficiency Virus Type 1

Cohen

Bianco

Connan

et al. 2002

J Virol

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“…To support this hypothesis, it has been clearly established for many years that the conjugation of a peptide with a lipid moiety strongly enhances immune responses (37). Moreover, HIV lipopeptide vaccines have been recently shown to induce HIV-specific CD4 and CD8 responses, at least in non-HIV-infected volunteers (38). Finally, studies in mice in vivo have reported that lipidated, but not nonlipidated vaccines induce protection against influenza virus or the intracellular bacterium L. monocytogenes (39).…”

Section: Discussionmentioning

confidence: 99%

TLR2 Engagement on CD8 T Cells Enables Generation of Functional Memory Cells in Response to a Suboptimal TCR Signal

Mercier

Cottalorda

Coupet

et al. 2009

The Journal of Immunology

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TLR are involved in the detection of microbial infection as well as endogenous ligands that signal tissue and cell damage in mammals. This recognition plays an essential role in innate immune response and the initiation of adaptive immune response. We have previously shown that murine CD8 T cells express TLR2, and that costimulation of Ag-activated CD8 T cells with TLR2 ligands enhances their proliferation, survival, and effector functions. We also demonstrated that TLR2 engagement on CD8 T cells significantly reduces their need for costimulatory signals delivered by APC. We show in this study that TLR2 engagement on CD8 T cells lowers the Ag concentration required for optimal activation, and converts a partial activation into a productive process leading to a significant expansion of cells. Using altered peptide ligands, we demonstrate that TLR2 engagement increases CD8 T cell activation and enables the generation of functional memory cells in response to a low TCR signal. This increased activation is associated with an augmented activation of the PI3K. Taken together, our results demonstrate that TLR2 engagement on CD8 T cells lowers their activation threshold for TCR signal strength and enables efficient memory cell generation in response to a weak TCR signal.

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“…Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15]. The current report summarizes the phase 1 clinical safety and tolerability data, highlighting local and *Address correspondence to: Jeff Kennedy, M.D., Division of Molecular Medicine, Wadsworth Center, Biggs Laboratory, ESP, C606, NYS Department of Health, P.O.…”

Section: Hiv; Vaccine; Adverse Event; Vasculitismentioning

confidence: 99%

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

Kennedy

Green

et al. 2008

Vaccine

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This report describes the safety observations following administration of a polyvalent DNA primeprotein boost HIV-1 vaccine formulated with adjuvant QS21. Local injection site reactionswere the most common (65% of subjects), and included type IV delayed-type hypersensitivity (DTH) reactions at prior DNA inoculation sites in 12 of 28 (43%) subjects following protein vaccination. Systemic reactions revealed two cases of vasculitis temporally related to inoculation with recombinant Env protein + QS21 adjuvant. Questions remain regarding the cause of the vasculitis, but the unique DTH observation may have contributed to the high level of immune responses previously reported for this vaccine. Keywords HIV; vaccine; adverse event; vasculitisOver the past two decades, various HIV vaccines have been tested for safety and several for efficacy in humans. However, the majority have not reproduced, in humans, the high immunogenicity seen in preclinical testing. Recently, we reported that a novel multi-gene, polyvalent DNA prime-recombinant protein boost HIV vaccine formulation, DP6-001, elicited strong and balanced humoral and cell-mediated immunity in healthy, HIV-1-negative adult subjects [1]. Preclinical testing of DP6-001 demonstrated no significant adverse reactions in either rabbits or non-human primates despite the induction of robust immunity [2,3]. Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15]. The current report summarizes the phase 1 clinical safety and tolerability data, highlighting local and *Address correspondence to: Jeff Kennedy, M.D., Division of Molecular Medicine, Wadsworth Center, Biggs Laboratory, ESP, C606, NYS Department of Health, P.O. Box 509, Albany, New York 12201-0509, P: 518-473-8421, F: 518-473-2900, E: jsk07@health.state.ny.us. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The clinical trial was an open-label, 3-arm design requiring each subject to receive two vaccine components; three sequential inoculations using a DNA plasmid vaccine administered either intradermally (ID) or intramuscularly (IM) followed by two sequential inoculations using a protein vaccine as shown in Table 1. Healthy HIV-negative adults (aged 18-50) were enrolled under informed consent as previously described [1]. This study involved 2 dose levels of DNA vaccines (1.2mg (Groups A and B); 7.2mg (Group C)) expressing five gp120 Env ant...

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Lipopeptides induce cell-mediated anti-HIV immune responses in seronegative volunteers

Abstract: Lipopeptides are promising immunogens for an AIDS vaccine.

Cited by 76 publications

References 26 publications

Study of Antigen-Processing Steps Reveals Preferences Explaining Differential Biological Outcomes of Two HLA-A2-Restricted Immunodominant Epitopes from Human Immunodeficiency Virus Type 1

Study of Antigen-Processing Steps Reveals Preferences Explaining Differential Biological Outcomes of Two HLA-A2-Restricted Immunodominant Epitopes from Human Immunodeficiency Virus Type 1

TLR2 Engagement on CD8 T Cells Enables Generation of Functional Memory Cells in Response to a Suboptimal TCR Signal

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

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