Prevention of vaginal and rectal herpes simplex virus type 2 transmission in mice: mechanism of antiviral action

Abstract

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.

Cationic Dendrimer G2-S16 Inhibits Herpes Simplex Type 2 Infection and Protects Mice Vaginal Microbiome

“…The specific design and the three-dimensional structure of the G2-S16 dendrimer are essential features to interfere with envelope proteins of HIV-1 or HSV-2 and receptors on the host cells, conferring a multifactorial and nonspecific ability. Many in vitro and in vivo studies confirmed the safety and efficacy of this G2-S16 dendrimer to prevent HSV-2 and HIV-1 infections [17,19]. The G2-S16 dendrimer was stable at various pHs and in the presence of seminal fluids maintaining the anti-HIV-1 activity overtime, this dendrimer did not generate any type of drug resistance and did not cause inflammation or irritation in the vaginal mucosa after administration of G2-S16 dendrimer at various concentrations and different times in female mice and rabbits [17,19,20].…”

“…Many in vitro and in vivo studies confirmed the safety and efficacy of this G2-S16 dendrimer to prevent HSV-2 and HIV-1 infections [17,19]. The G2-S16 dendrimer was stable at various pHs and in the presence of seminal fluids maintaining the anti-HIV-1 activity overtime, this dendrimer did not generate any type of drug resistance and did not cause inflammation or irritation in the vaginal mucosa after administration of G2-S16 dendrimer at various concentrations and different times in female mice and rabbits [17,19,20]. When BALB/c mice or humanize (h)-BLT mice were pre-treated with topical 3% G2-S16 dendrimer and then female vaginally exposed to R5-HIV-1 JR-CSF or HSV-2 333, G2-S16 dendrimer efficiently prevented female vaginal HIV-1 transmission by 84% [19] and HSV-2 by 100% [17].…”

“…The G2-S16 dendrimer was stable at various pHs and in the presence of seminal fluids maintaining the anti-HIV-1 activity overtime, this dendrimer did not generate any type of drug resistance and did not cause inflammation or irritation in the vaginal mucosa after administration of G2-S16 dendrimer at various concentrations and different times in female mice and rabbits [17,19,20]. When BALB/c mice or humanize (h)-BLT mice were pre-treated with topical 3% G2-S16 dendrimer and then female vaginally exposed to R5-HIV-1 JR-CSF or HSV-2 333, G2-S16 dendrimer efficiently prevented female vaginal HIV-1 transmission by 84% [19] and HSV-2 by 100% [17]. However, determine the role of G2-S16 dendrimer against HSV-2 infection in presence of semen must be studied since it has been reported that the presence of semen enhances HSV-2 infection in a 10 fold rate [21].…”

“…Semen samples of healthy men donors were obtained after informed consent [22] as described before [15,17]. The semen samples were aliquots at −20 • C for further experiments.…”

“…Our group has shown that one of the most promising microbicides could be the G2-S16 polyanionic carbosilane dendrimer [15,16]. The potent activity of this G2-S16 dendrimer against HIV-1 and HSV-2 has been demonstrated [17][18][19]. The G2-S16 dendrimer is a second-generation dendrimer with a carbosilane structure containing 16 sulfonate peripheral groups derived from a silicon core [16].…”