The phosphorus dendrimers cannot be used as vaccines because they would not have the ability to induce an immune response. The cationic phosphorus dendrimers associated with HIV-derived peptides have the ability to deliver peptides as non-viral vectors. However, there are other potential therapeutic applications of these compounds, for instance as topical antiinflammatory agents, as compounds for allograft rejection or autoimmune diseases and as agents inducing specific tolerance with antigen-loaded DC against allergy reaction. Nevertheless, these applications need to be evaluated.
Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH–gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.
Although the antiretroviral therapy has led to a long-term control of HIV-1, it does not cure the disease. Therefore, several strategies are being explored to develop an effective HIV vaccine, such as the use of dendritic cells (DCs). DC-based immunotherapies bear different limitations, but one of the most critical point is the antigen loading into DCs. Nanotechnology offers new tools to overcome these constraints. Dendrimers have been proposed as carriers for targeted delivery of HIV antigens in DCs. These nanosystems can release the antigens in a controlled manner leading to a more potent specific immune response. This review focuses on the first steps for clinical development of dendrimers to assess their safety and potential use in DC-based immunotherapies against HIV.
Dendrimers are highly branched, star-shaped, and nanosized polymers that have been proposed as new carriers for specific HIV-1 peptides. Dendritic cells (DCs) are the most-potent antigen-presenting cells that play a major role in the development of cell-mediated immunotherapy due to the generation and regulation of adaptive immune responses against HIV-1. This article reports on the associated behavior of two or three HIV-derived peptides simultaneously (p24/gp160 or p24/gp160/NEF) with cationic carbosilane dendrimer G2-NN16. We have found that (i) immature DCs (iDCs) and mature (mDCs) did not capture efficiently HIV peptides regarding the uptake level when cells were treated with G2-NN16-peptide complex alone; (ii) the ability of DCs to migrate was not depending on the peptides presence; and (iii) with the use of molecular dynamic simulation, a mixture of peptides decreased the cell uptake of the other peptides (in particular, NEF hinders the binding of more peptides and is especially obstructing of the binding of gp160 to G2-NN16). The results suggest that G2-NN16 cannot be considered as an alternative carrier for delivering two or more HIV-derived peptides to DCs.
Nanotechnology-derived platforms, such as dendrimers, are very attractive in several biological applications. In the case of human immunodeficiency virus (HIV) infection, polyanionic carbosilane dendrimers have shown great potential as antiviral agents in the development of novel microbicides to prevent the sexual transmission of HIV-1. In this work, we studied the mechanism of two sulfated and naphthylsulfonated functionalized carbosilane dendrimers, G3-S16 and G2-NF16. They are able to inhibit viral infection at fusion and thus at the entry step. Both compounds impede the binding of viral particles to target cell surface and membrane fusion through the blockage of gp120–CD4 interaction. In addition, and for the first time, we demonstrate that dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation. Thus, carbosilane dendrimers’ mode of action is a multifactorial process targeting several proteins from viral envelope and from host cells that could block HIV infection at different stages during the first step of infection.
Methods: We used XTT assay to define non-cytotoxic concentrations of GRFT, ZA, CG or their combinations. Assays for anti-HIV, anti-HPV and anti-HSV-2 activities were performed in TZM-bl cells or PBMCs using MAGI and p24 ELISA; in HeLa cells using a luciferase assay; and in Vero cells using plaque forming units (pfu) assay. We performed time-of-addition and temperature dependence experiments to differentiate inhibition of viral adsorption from entry. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins and immunohistochemistry was used to determine the specific glycoprotein involved. Antiviral activities of prototype GRFT/CG (GC) and GRFT/ZA/CG (GZC) gels in a vaginal HSV-2 mouse model were evaluated. Results: GRFT shows modest in vitro antiviral activity against HSV-2 G (IC 50 = 5.8lg/ml) and HPV 6, 16, 18, 45 PsVs (IC 50 = 10.8-26.3lg/ml), compared to potent anti-HIV activity (IC 50 = 0.7-1.4ng/ml). As with HIV, GRFT blocks the entry but not the adsorption of HSV-2 and HPV to target cells. The combined analyses of SPR and immunohistochemistry for HSV-2 gD, suggest that GRFT binds to HSV-2 gD. GC and GZ had synergistic in vitro antiviral activity against HIV and HPV (CI < 1). GC and GZC gels significantly reduced (p < 0.05) HSV-2 vaginal infection in vivo when administered up to 2h before challenge with 10 6 pfu/mouse. Conclusions: GRFT blocks HSV-2 and HPV entry to target cells and combination with CG and/or ZA may result in a potent/ broad-spectrum non-ARV microbicide.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.