Nanotechnology offers novel suitable tools in order to develop new therapies and preventive strategies against HIV, such as dendrimers. The developments of a safe and effective microbicide to prevent the sexual transmission of HIV-1 is urgently needed. The use of dendrimers as vaginal microbicides is a promising prevention strategy against sexually transmitted infections. We selected G2-S16, (C112H244N8Na16O48S16Si13; Mw = 3,717.15 g/mol), a second generation carbosilane dendrimer with 16 sulfonate groups in the periphery. We show that topical vaginal administration of 3% G2-S16 prevents HIV-1JR-CSF transmission in humanized (h)-BLT mice without irritation or vaginal lesions. G2-S16 exerts anti-HIV-1 activity at an early stage of viral replication, as a virucidal agent and blocking the gp120/CD4 interaction. G2-S16 adheres to host cell-surface proteins. We also demonstrate the dendrimer’s capability to provide a barrier to infection for long periods, confirming its multifactorial and non-specific ability. This study represents the first demonstration that transmission of HIV-1 can be efficiently blocked by vaginally applied G2-S16 anionic carbosilane dendrimer. On the other hand, it is essential that prophylactic drugs do not interfere with the normal function of the immune system. We essay the effects of G2-S16 on the immune barrier of the female reproductive tract. The expression of differentiation, maturation and activation markers has been measured in epithelial cells (VK2), dendritic cells, M and GM macrophages, and T cells using RT-qPCR and flow cytometry. Previous results demonstrate that our dendrimer does not alter the natural immunity of the vagina, strongly supporting the biosafety of its for clinical use. However, the vaginal microbiota comprised a wide variety of bacterial species that aids to maintain a healthy microenvironment with the host cells. Alterations in the composition of this ecosystem could lead to a higher risk to acquire sexually transmitted infections. We report the effect of G2-S16 on mice vaginal microbiota in the context of HSV-2 infection. Our results prove that G2-S16 prevents the alteration of this microenvironment in the presence of HSV-2, being a candidate for further assays up to a clinical trial. Finally, we are assessing the effectiveness of G2-S16 to prevent infection by HIV-1 or HSV-2 in explants of human vaginal tissue obtained after its expansion from samples from ectocervix and endocervix from healthy women aged between 18 and 50 years of age from a scheduled hysterectomy for prolapse and/or uterine myoma.
Dra. Mª Angeles Muñoz-Fernández
Hospital General Universitario Gregorio Marañón, CIBER BBN, Spanish HIV HGM BioBank
Martes, 07 Mayo 2019 12:00