P33.04
Background: Topical microbicides are researched as potential tools in order to stop the HIV sexual spreading in all risk groups. Since the majority of clinical trials in HIV-1 patients have failed, nanotechnology offers novel suitable approaches to develop new microbicidal compounds, such as dendrimers.
Methods: In vitro and in vivo studies were performed to evaluate the safety, biocompatibility, anti-HIV ability and mechanism of two polyanionic carbosilane dendrimers. Moreover, the antiviral activity of carbosilane dendrimer/ARV combinations against R5, X4 and dual tropic HIV-1 isolates was evaluated in human primary cells and TZM.bl cell line using Calcusyn software.
Results: Sulphated and naphthylsulfonated functionalized carbosilane dendrimers G3-S16 and G2-NF16 are shown as safety and effective compounds against HIV. They impede laboratory and clinical primary HIV-1 isolates infection in activated PBMC and inhibit HSV-2 infection in vitro. Dendrimers are able to inhibit viral infection at fusion and thus at the entry step. They impede the binding of viral particles to target cells surface and membrane fusion, through the blockage of gp120/CD4 interaction. In addition, dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation.
G3-S16 or G2-NF16 did not produce changes in proinflammatory cytokines profile in treated epithelial cells, in PBMC proliferation, microbiota or sperm survival. Moreover, no irritation, inflammation or vaginal lesions were detected in female mice after dendrimers vaginal administration.
As well, G3-S16 and G2-NF16 showed a synergistic activity profile with AZT, efavirenz, maraviroc and tenofovir in the majority of combinations tested against X4 and R5 tropic HIV-1 in cell lines as well as in primary human cells.
Conclusions: Carbosilane dendrimers and their combinations with ARV can be effective antiviral agents, supporting further clinical research on these as potential microbicides in the context of blocking HIV-1 sexual transmission.
