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  • Intranasal immunization can induce the activation


    Intranasal immunization can induce the activation of IgA-secreting plasma cell precursors that are present in NALT and induce IgA antibody-secreting cells; these cells express l-selectin (+), allowing migration to the lymphatic nodes, as well as α4β1 (+), CXCR4 (+), and CCR10 (+), which facilitate migration from the NALT to VCAM-1 (+) and CCL28 (+) genital mucosa [53]. This process explains the origin of IgA and IgM in the nasal mucosa and vaginal mucosa. The presence of IgG and IgM in vaginal lavages may be attributable to the transudation of IgG and IgM from the serum [54]. The adjuvant effect of the dendrimers has been previously attributed to peptide solubility enhancement, controlled release peptide kinetics, increased antigen uptake and the enzymatic protection of peptide degradation [12], improving the in vitro production of TNF-α, MIP-2 and IL-6, [55] and the capability of G4-PAMAM dendrimers to remain in the nasal mucosa barrier for a longer time, increasing the bioavailability of the carrier peptides (PGV04 or ABC) because the cationic PAMAM dendrimer G4 (terminal primary amine, pKa 7.0–9.0 and tertiary amine pKa 3.0–6.0) [56] can be coupled noncovalently to anionic sialic PHA 543613 hydrochloride receptor residues (carboxylic acid, pKa 2.6) [57] from the mucosal barrier in the nasal epithelium (pH 5.5–6.5) [58], as previously reported for chitosan, a cationic mucoadhesive nanoparticle that also has surface primary amines (pKa 6.5) [59].
    Conclusions Peptide epitopes from the CD4 binding site located in gp120-HIV-1 can be identified using in silico tools and nanotechnology approaches to enhance peptide immunogenicity. G4-PAMAM dendrimer-peptide complexes can be modeled through molecular docking simulations. Thus, molecular docking and MD simulations coupled with the MMGBSA approach, peptide physicochemical property prediction, biophysical characterization and the application of molecular dissociation allowed us to make a rational design that reduced time and cost. G4-PAMAM dendrimers can be used simultaneously as relative nontoxic nanocarriers and adjuvants of peptides for intranasal administration in female BALB/c mice to enhance systemic immunogenicity.
    Conflict of interest
    Acknowledgements The work was supported by grants from CONACYT (CB-254600, CB-241339 and PDCPN-782), CYTED: 214RT0842, scholarships from CONACYT. Centro de Nanociencias y Micro y Nanotecnologías del Instituto Politécnico Nacional (
    Introduction Primate lentiviruses (PLV) are known to include the simian immunodeficiency viruses (SIVs) along with the human immunodeficiency viruses type 1 (HIV-1) and type 2 (HIV-2) which have posed a major threat to human health globally in the 21st century (Centers for Disease, C., Prevention, 2006, Dore, 2000, Hahn et al., 2000, Locatelli and Peeters, 2012). It is known that the human immunodeficiency viruses (HIV-1 and HIV-2) entered the human population through cross-species transmissions of SIVs around the turn of the twentieth century (Compton et al., 2013, Gao et al., 1999, Hillis, 2000, Sharp and Hahn, 2011, Takehisa et al., 2009). Four independent transmission events have given rise to HIV-1 groups M, N, O and P (Sharp and Hahn, 2011). A separate lentiviral lineage, HIV-2, emerged in humans at least eight times via cross-species transmissions from simian immunodeficiency viruses of sooty mangabey monkeys (SIVsm) (Gao et al., 1992, Hirsch et al., 1995). There are at least forty SIV species found in African monkeys which have a great potential to continually jump to humans (Sharp and Hahn, 2010, Sharp et al., 2013). Therefore, it is very important to understand PLV pathogenesis, evolution and transmission. During the past three decades, tremendous efforts have been made in the fight against the HIV-1 major group M epidemic. Particularly, there has been extensive effort to understand the envelope spike, which is the sole viral protein on the surface of HIV virions and plays a critical role in viral infection, evolution and transmission. The envelope spike has been known to have a trimeric structure for decades, but the structure of the envelope trimer was not solved until 2013 (Julien et al., 2013, Lyumkis et al., 2013). According to the envelope trimer structures reported, the major loops V1, V2 and V3 of gp120 are packed into the apex of envelope trimer, which is essential for the loops contribution to trimeric stabilization (Do Kwon et al., 2015, Julien et al., 2013, Lyumkis et al., 2013, Pancera et al., 2014). Another important finding from vaccine clinical trials is that the V2 loop has been found to be an important immunogen in the RV144 vaccine trial by inducing neutralizing antibodies (de Souza et al., 2012, Karasavvas et al., 2012, Kim et al., 2015, van Gils et al., 2011). Previously, we PHA 543613 hydrochloride receptor reported that the twin-cysteine motif (TCM) in the V2 loop region of gp120 in the SIVmac239 strain plays an important role in the stabilization of the envelope trimer (Bohl et al., 2013). Substitution of the cysteines singly or doubly causes drastic gp120 shedding and leads to reduced viral infection. Based on envelope sequence alignment of primate lentiviruses, the twin-cysteines are present in all SIV and HIV-2 strains but not in HIV-1 strains. More interestingly, in SIVcpz, some strains have the TCM, such as SIVcpzANT, while others do not, such as SIVcpzTAN. According to the PLVs evolutionary relationship, it is apparent that the SIVcpz strains are close to HIV-1 which do not contain the TCM. This strongly suggests that the TCM was lost in the SIVcpz and HIV-1 strains during the viral evolution process. However, in the SIVsm, SIVmac and HIV-2 lineages, the TCM is maintained. This raises a very interesting question about the importance of the TCM in PLVs and whether this TCM is associated with HIV pathogenesis or transmission. Thus, in this project, we have studied the role of the TCM in different SIV isolates and in HIV-2, in which the twin-cysteines are preserved. To further support our hypothesis we have also introduced the twin-cysteines back to HIV-1 strains to observe the effect of the TCM in HIV-1 strains, which is significant for envelope based vaccine immunogen design.