HIV-derived vectors for therapy and vaccination against HIV.

Despite being at the origin of one of the world's most devastating public health concerns, the Human Immunodeficiency Virus (HIV) has properties that can be harnessed for therapeutic purposes. Indeed, the ability of HIV to efficiently deliver its genome into the nuclear compartment makes it an ideal vector for gene delivery into target cells. The design of so-called HIV-derived vectors, or more generally lentiviral vectors (LVs), consists in keeping only the parts of the virus that ensure efficient nuclear delivery while entirely removing all coding sequences that contribute towards the replication and pathogenesis of the virus: as a result, the vector genome is composed of less than 10% of the original virus genome and exclusively cis-active sequences. Proteins required for the formation of the lentivector particles and for the early steps of viral replication (including Gag- and Pol-derived proteins) are provided in trans. HIV-derived vectors are thus non-replicative virus shells that deliver genes of interest into target cells with high efficiency. Undoubtedly, there is a hopeful twist of fate in our fight against AIDS, which consists in using these vectors to achieve gene therapy and vaccination against HIV itself. This review summarises the current generation of LVs with a special focus on vaccine applications against AIDS. Preclinical data are very encouraging and efforts are ongoing to optimise these vectors, to increase their safety and improve their immunogenicity.

Apoptotic cells at the crossroads of tolerance and immunity.

Clearance of apoptotic cells by phagocytes can result in either anti-inflammatory and immunosuppressive effects or prostimulatory consequences through presentation of cell-associated antigens to T cells. The differences in outcome are due to the conditions under which apoptosis is induced, the type of phagocytic cell, the nature of the receptors involved in apoptotic cell capture, and the milieu in which phagocytosis of apoptotic cells takes place. Preferential ligation of specific receptors on professional antigen-presenting cells (dendritic cells) has been proposed to induce potentially tolerogenic signals. On the other hand, dendritic cells can efficiently process and present antigens from pathogen-infected apoptotic cells to T cells. In this review, we discuss how apoptotic cells manipulate immunity through interactions with dendritic cells.

Immunity under the skin: potential application for topical delivery of vaccines.

With the technological advances in biomedical sciences and the better understanding of how the immune system works, new immunisation strategies and vaccine delivery options, such sprays, patches, and edible formulations have been developed. This has opened up the possibility of administering vaccines without the use of needles and syringes. Already topical immunisation is a reality and it has the potential to make vaccine delivery more equitable, safer, and efficient. Furthermore, it would increase the rate of vaccine compliance and greatly facilitate the successful implementation of worldwide mass vaccination campaigns against infectious diseases. This review gives a brief account of the latest developments of application of candidate vaccine antigens onto bare skin and describes some of our recent observations using peptide and glycoconjugate vaccines as immunogens.

The LTR72 mutant of heat-labile enterotoxin of Escherichia coli enhances the ability of peptide antigens to elicit CD4(+) T cells and secrete gamma interferon after coapplication onto bare skin.

Application of antigens with an adjuvant onto bare skin is a needle-free and pain-free immunization procedure that delivers antigens to the immunocompetent cells of the epidermis. We tested here the immunogenicity and adjuvanticity of two mutants of heat-labile enterotoxin (LT) of Escherichia coli, LTK63 and LTR72. Both mutants were shown to be immunogenic, inducing serum and mucosal antibody responses. The application of LTK63 and LTR72 to bare skin induced significant protection against intraperitoneal challenge with a lethal dose of LT. In addition, both LT mutants enhanced the capacity of peptides TT:830-843 and HA:307-319 (representing T-helper epitopes from tetanus toxin and influenza virus hemagglutinin, respectively) to elicit antigen-specific CD4(+) T cells after coapplication onto bare skin. However, only mutant LTR72 was capable of stimulating the secretion of high levels of gamma interferon. These findings demonstrate that successful skin immunization protocols require the selection of the right adjuvant in order to induce the appropriate type of antigen-specific immune responses in a selective and reliable way. Moreover, the use of adjuvants such the LTK63 and LTR72 mutants, with no or low residual toxicity, holds a lot of promise for the future application of vaccines to the bare skin of humans.

Immunization onto bare skin with heat-labile enterotoxin of Escherichia coli enhances immune responses to coadministered protein and peptide antigens and protects mice against lethal toxin challenge.

In this study, the potential of the bare skin as a non-invasive route for vaccination was examined. Following application of heat-labile enterotoxin (LT) of Escherichia coli onto bare skin of BALB/c mice, strong serum anti-LT antibody responses were observed, and mucosal immunoglobulin A (IgA) and IgG antibodies were measured in vagina washes. In addition, LT enhanced the serum and mucosal antibody and proliferative T-cell responses to the model protein antigen beta-galactosidase (beta-gal) when coadministered onto bare skin, highlighting its potential to exert an adjuvant effect. When a peptide representing a T-helper epitope (aa 307-319) from the haemagglutinin of influenza virus was applied onto bare skin with LT or cholera toxin (CT), it primed effectively peptide- and virus-specific T cells, as measured in vitro by the interleukin-2 (IL-2) secretion assay. LT was shown to be as immunogenic as CT. Binding activity to GM1 gangliosides was essential for effective induction of anti-CT serum and mucosal antibody responses. Finally, mice immunized onto bare skin with LT were protected against intraperitoneal challenge with a lethal dose of the homologous toxin. These findings give further support to a growing body of evidence on the potential of skin as a non-invasive route for vaccine delivery. This immunization strategy might be advantageous for vaccination programmes in Third World countries, because administration by this route is simple, painless and economical.

The bare skin and the nose as non-invasive routes for administering peptide vaccines.

Among the different technologies currently tested for the development of novel vaccines, synthetic peptides represent a promising option, since they are chemically pure and induce immune responses of predetermined specificity. Furthermore, they can be replaced with pseudopeptides or peptide mimetics that contain changes in the amide bond, resulting in more stable and immunogenic molecules. Administration of peptide vaccines via non-invasive routes, such as the nose or the bare skin, allows the efficient uptake of antigen by antigen-presenting cells, which are abundant in the associated lymphoid tissues, ensuring the induction of effective systemic and mucosal immune responses. Using non-invasive routes could be advantageous for vaccination programs in third-world countries, since vaccine administration is simple, painless and economical. In this review, we discuss and present some preliminary data on the advantages of synthetic peptides and peptidomimetics as candidate vaccines, and their potential for administration via the skin and the nose.