Resumen de Polyanionic dendritic nanoparticles against human immunodeficiency virus Type 1 and herpes simplex virus Type 2: searching for microbicides and new therapeutic approaches
In spite of the significant efforts to develop effective vaccines against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2), they still remain elusive and microbicides have emerged as a feasible preventive strategy against both viruses. Up to date, several topically applied compounds have failed and the search of new candidates is urgently needed. Polyanionic dendritic nanoparticles, such as dendrons showed unique chemical properties that could be effective against both HIV-1 and HSV-2. We performed a screening of six polyanionic carbosilane dendrons with fatty acid at the core. Results concluded that only the third generation dendrons with hexanoic or palmitic acid at the core exerted a great broad-spectrum antiviral activity, as well as a suitable efficacy against HIV-1 even if the mucosal disruption occurs as consequence of HSV-2 infection. Third generation dendrons retained their antiviral properties at different pHs and remained capable of blocking HIV-1 and HSV-2 infections at early stages of viral cycles. Unfortunately, the study of their vaginal in vivo toxicity in BALB/c mice revealed that they were not safe.
Previous studies in our laboratory revealed the potent activity of G1-S4, G2-S16 and G3-S16 polyanionic carbosilane dendrimers against HIV-1 and HSV-2 by themselves and in combination with several antiretrovirals, such as tenofovir (TFV) or maraviroc (MVC). We further go deep into these studies using dapivirine (DPV), a leading antiretroviral candidate showing good results on HIV-1 prevention in phase III human clinical trials. The combination of dendrimers, acting at the very first stages of infection together with DPV, which interferes HIV-1 reverse transcriptase (RT), resulted in more than 95% of R5-HIV-1NLAD8 inhibition with synergistic or additive profiles. We also proved that dendrimer/DPV combination inhibited the HIV-1 infection without altering the potent activity of dendrimers to prevent other viral infections, such as HSV-2. Interestingly enough, dendrimers and DPV did not modify the growth of several bacteria strains in vitro. The vaginal microbiome comprised a wide variety of bacterial species and alterations in this ecosystem could lead to higher risk to acquire sexually transmitted infections (STIs), such as HSV-2 and HIV-1. We selected the G2-S16 dendrimer as the leading candidate to further evaluate its effect on vaginal microbiome using BALB/c mice in the context of HSV-2 infection. We characterized the composition of mice vaginal microbiome by a metagenomic approach and reported a significant shift in that microbiome after HSV-2 infection. We proved that G2-S16 prevented this alteration, both in the presence or absence of HSV-2, supporting further assays up to a possible clinical trial.
New therapeutic applications of dendrimers are being studied. In this context, the study of G1-S4, G2-S16 and G3-S16 dendrimers in the X4-HIV-1 tropic cell-cell fusion process, referred to syncytium formation, remains still unknown. Dendrimers prevented the X4-HIV-1 infection, as well as syncytia formation, in a dose-dependent manner. We demonstrated that G2-S16 and G1-S4 reduced significantly syncytia formation in HIV-1 Env-mediated cell-to-cell fusion model. These results were supported by in silico molecular modeling which revealed that G2-S16 dendrimer interfered with gp120-CD4 complex, demonstrating its new and potential use not only as potential microbicides but also as a HIV-1 treatment.
