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  • The use of HIV peptide epitope based vaccines

    2021-09-23

    The use of HIV-1 peptide epitope-based vaccines is safer and cheaper than live or inactivated vaccines [8]. However, peptide epitope vaccines could show poor immunogenicity and have poor uptake by APCs [9]. Nevertheless, nanocarrier-based delivery platforms have been demonstrated to enhance the peptide-specific immune response by acting as adjuvants [10] and enhancing antigen uptake by APCs [11]. In this regard, fourth-generation polyamidoamine (G4-PAMAM) dendrimers have been used as nanocarriers for chlamydia synthetic peptide vaccines administered by an intranasal route, showing the enhancement of an immune peptide-specific response in the vaginal mucosa and serum of female mice [12]. Nasal immunization induces both mucosal and systemic immunity using different vaccines [13]. Nasal immunization is an interesting strategy to induce a gp120-specific immune response and has been used to induce HIV-1 peptide C4/V3 T1SPMN-specific ck2 inhibitor in the serum and vaginal mucosal [14]. In our study, we identified and evaluated two peptide epitopes (PGV04 and ABC), either alone or in complex with G4-PAMAM dendrimers, using the three-dimensional (3D) model gp120 from the BG505 SOSIP trimer model (PDB: 3J5M) as a source of peptide epitopes. The G4-PAMAM dendrimer-PGV04 peptide and G4-PAMAM dendrimer-ABC peptide complexes were built using in silico procedures and validated via experimental procedures in which the complexes were administered by an intranasal route to BALB/cJ female mice to measure IgG, IgA and IgM responses in nasal and vaginal washes and serum.
    Materials and methods
    Results
    Discussion ABCpred identified an ABC peptide epitope that was not hidden in the gp120-gp120 or gp41-gp120 interface and was intriguingly located in the CD4B domain of gp120-FAb PGV04 close to the peptide epitope PGV04. The CD4b domain is considered a region of vulnerability in the HIV infection [6]. Thus, the utility of ABCpred and in silico dissociation for predicting epitopes in the CD4bs domain of quaternary gp120 was demonstrated. The structural complementarity of peptide conformers and the inner surfaces of the nonpolar cavities of G4-PAMAM dendrimers allows the internalization of the peptide conformers. Thus, the number and volume of these cavities in the G4-PAMAM dendrimer determine its ability to accommodate a specific number of ligands, such as peptide molecules. Additionally, the presence of negative partial charges in ligands is important for the formation of peptide-dendrimer complexes with the cationic dendrimer G4-PAMAM (NH3+) [49,50]. In silico procedures were the first step to identify ratios similar to those reported in previous to peptide-dendrimer complex formation, reversibility and toxicity assays. The ABC- and PGV04-dendrimer complexes morphologies are most likely attributed to supramolecular effects due to the modification of the electrical charges of the G4-PAMAM dendrimer [49,50]. This finding was consistent with previous studies carried out with G4-PAMAM dendrimers and anionic ligands [51]. In addition, the formation of 1:1 μM peptide-dendrimer complexes was confirmed by differences in the MALDI-TOF spectra of single G4-PAMAM dendrimers and 1:1 μM G4-PAMAM dendrimer-ABC and G4-PAMAM dendrimer-PGV04 complexes. However, due to MALDI-TOF spectra showing light signals (Fig. 9), despite the results of other reports [51]. Additionally, to show experimentally the peptide recognition on G4-PAMAM dendrimer we include 1H NMR, identifying that G4-PAMAM dendrimer signals are affected in the presence of the peptides (Fig. 10), as has been reported for other ligand-G4-PAMAM complexes [52]. These NMR signals that decreased in presence of peptides are due to hydrogen bonds with H of amide group (≅ 8 ppm), H of methylene groups (R2CH2 = 2.36–2.39 ppm, −CH2CO-R = 2.64–2.69 ppm) among others (Fig. 10). Thus, our results suggest that peptides are capable to reach the G4-PAMAM internal cavities as was depicted by docking and MD simulations (Fig. 6, Fig. 7). In our study, the ABC and PGV04 peptides alone or in complex with the G4-PAMAM dendrimer were immunogenic, mainly inducing a high IgA response in the vaginal mucosa and IgG and IgM responses in serum samples. These results agree with other studies reporting that gp120 epitopes (C4/V3 peptide epitope of HIV-1) administered by the nasal route can elicit vaginal, nasal and systemic responses with single peptides or with the coadministration of two adjuvants (CT or Cry1Ac) [14].