Two Human Immunodeficiency Virus Vaccinal Lipopeptides Follow Different Cross-Presentation Pathways in Human Dendritic Cells

Abstract

An efficient vaccine against human immunodeficiency virus (HIV) must induce good cellular immune responses. To do this, it must be processed and presented by dendritic cells, which are required for primary T-lymphocyte stimulation. We have previously shown that a model lipopeptide containing a short epitopic peptide from HIV-1 was endocytosed and presented in association with major histocompatibility complex class I molecules by human dendritic cells to specific CD8 ؉ T lymphocytes, but the cross-presentation pathway needed to be precisely determined. We have studied a longer lipopeptide (Pol 461-484 ) and another lipopeptide (Nef 66-97 ) currently being used in vaccine trials. Like the shorter lipopeptide, the rhodamine-labeled Pol 461-484 lipopeptide was internalized by endocytosis, as assessed by confocal microscopy. The lipopeptides were processed by dendritic cells and presented to CD8 ؉ T cells specific for the HLA-A*0201-restricted Pol 476-484 and the HLA-A*0301-restricted Nef 73-82 epitope, respectively. Presentation of both lipopeptides was inhibited by brefeldin A. Presentation of the Pol lipopeptide was inhibited by epoxomycin, a proteasome-specific inhibitor, but not by monensin. This shows that it gained access to the cytosol to be digested by the proteasome. In contrast, presentation of the Nef lipopeptide was not inhibited by epoxomycin but was inhibited by monensin, a classical inhibitor of acid-dependent endosomal enzyme activity, indicating an endocytic processing pathway yielding to major histocompatibility complex class I-restricted presentation. Therefore, the two lipopeptides followed different cross-presentation pathways, both resulting in efficient presentation to CD8 ؉ T lymphocytes.

Long-Term Multiepitopic Cytotoxic-T-Lymphocyte Responses Induced in Chimpanzees by Combinations ofPlasmodium falciparumLiver-Stage Peptides and Lipopeptides

“…Several LS peptide epitopes selected in the present study induced CTL responses, indicating that each peptide defines at least one multirestricted CTL epitope or a series of adjacent or overlapping epitopes restricted by distinct class I molecules, thus underscoring the clinical potential for this set of LS peptides and lipopeptides. The present study confirms and extends recent findings of multiepitopic CD8 ϩ -CTL induction by human immunodeficiency virus-derived lipopeptides (4,5,28). In contrast to peptides linked to the complex immunostimulating tripalmitoyl-s-glyceryl-cysteinyl-seryl-serine moiety, which is both mitogenic and to some extent toxic (63), the lipopeptides modified by a single palmitoyl group used in the present study proved to be well tolerated.…”

Processing and Presentation of Exogenous HLA Class I Peptides by Dendritic Cells from Human Immunodeficiency Virus Type 1-Infected Persons

“…The results also indicate that intracellular uptake and processing are involved in the presentation of these exogenous 9-mer peptides to CD8 ϩ T cells by professional APCs. In this regard, Andrieu and colleagues (1,2) have recently reported that HIV-1 RT [476][477][478][479][480][481][482][483][484] or its N-terminal extension RT 461-484 when bound to a lipid (Nε-palmytoyl-lysine) is processed intracellularly by iDCs of HIV-1-negative subjects for presentation to CD8 ϩ T-cell lines. We found, however, that the APCs with the greatest capacity for activating peptide-specific CD8 ϩ T cells were mDCs.…”

Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct

“…The choice of this lipopeptide anchor is highly important for the immune response, since it allows the targeting, via poorly understood mechanisms (Uhl et al, 1991;Andrieu et al, 2003), of exogenous antigens into MHC class I and class II restricted pathways. Lipopeptides, such as Pam 3 CSS, constitute potent and nontoxic immunoadjuvants which, for example, activate B lymphocytes (Bessler et al, 1985) and APCs such as macrophages and DCs (Hertz et al, 2001).…”