No abstract

Paired sera and parotid saliva from 75 HIV‐1‐infected patients, divided in three equal groups with CD4+ cell counts > 500, 200–500 and < 200/mm3, respectively, were analysed for IgG, IgA and secretory IgA (sIgA) concentrations and for IgG and IgA antibody directed to HIV‐1. Twenty‐nine age‐matched HIV− subjects were used as controls. In serum the concentrations of immunoglobulins were significantly increased in HIV‐infected subjects compared with controls, and a progressive increase of IgA and sIgA was noticed while the CD4+ cell count decreased. In contrast, concentrations of IgA and sIgA were not different in parotid saliva between the four subject groups. By an ELISA test directed towards HIV‐1 proteins, 73 of the 75 serum specimens from the HIV‐infected subjects (97%) and 43 of the corresponding saliva (57%) were found positive for specific IgA antibodies to HIV‐1, with an even distribution among the three groups of patients. By Western blotting multiple specificities of IgA to HIV‐1 proteins were not frequently found in patients. By contrast, in spite of an IgG concentration in saliva about 100 times lower than that of IgA, reactivities were significantly higher for IgG than for IgA antibodies, especially to env and to pol HIV‐1 products. Altogether, these data suggest that the regulation of IgA production in HIV‐infected subjects is independent in serum and in parotid saliva. This imbalance of IgA/IgG antibodies to HIV‐1 at the mucosal level appears to be a specific feature of HIV‐1 infection, and may raise important issues in terms of local protection after immunization.

Recent investigations have suggested that pseudopeptides containing modified peptide bonds might advantageously replace natural peptides in therapeutic strategies. We have generated eight reduced peptide bond ⌿(CH 2 -NH) analogues corresponding to the H-2D b -restricted CD8؉ T cell epitope (called GP33) of the glycoprotein of the lymphocytic choriomeningitis virus. One of these pseudopeptides, containing a reduced peptide bond between residues 6 and 7 (⌿(6 -7)), displayed very similar properties of binding to major histocompatibility complex (MHC) and recognition by T cell receptor transgenic T cells specific for GP33 when compared with the parent peptide. We assessed in vitro and in vivo the proteolytic resistance of GP33 and ⌿(6 -7) and analyzed its contribution to the priming properties of these peptides. The ⌿(6 -7) analogue exhibited a dramatically increased proteolytic resistance when compared with GP33, and we show for the first time that MHC-peptide complexes formed in vivo with a pseudopeptide display a sustained half-life compared with the complexes formed with the natural peptide. Furthermore, in contrast to immunizations with GP33, three injections of ⌿(6 -7) in saline induced significant antiviral protection in mice. The enhanced ability of ⌿(6 -7) to induce antiviral protection may result from the higher stability of the analogue and/or of the MHC-analogue complexes.T cells recognize antigenic peptides in association with MHC 1 molecules and play a key role in protection against harmful pathogens and in tumor elimination. Over the past years many attempts have been made to use synthetic peptides as potential vaccines and immunoregulatory agents (1, 2). Recent studies have provided evidence that pseudopeptides, in which one or several of the natural amide bonds (CO-NH) are replaced by CO-NH isosters (3), can have enhanced antigenic and immunogenic properties (4 -6). Most interestingly, it has been shown that such peptide analogues can bind to class I and II MHC molecules (7-13), and some of them also induce differential effects on T cell responsiveness (14) similar to those described with altered peptide ligands, which contain single amino acid replacements (15). These several recent studies thus demonstrated the potential interest of pseudopeptides as possible therapeutic strategies in T cell-mediated disorders.The high susceptibility of synthetic peptides to proteases is considered to be a major drawback for their use as vaccines or immunoregulatory molecules (16). We have previously shown that several pseudopeptides with enhanced antigenic activity are more resistant to proteolytic degradation in vitro (5, 6, 14, 17). However, no information on in vivo stability of such peptide analogues and the possible direct contribution of this resistance in their ability to modulate the immune response is available. Increased biological activity of protease-resistant pseudopeptide analogues has already been widely shown in other fields of medical chemistry (for review, see Ref. 18,[19][20][21][22]. The retro...

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