The use of nanotechnology: polyanionic carbosilane dendrimers and antivirals as novel preventive methods against HIV-1 and HCV
- Autores: Daniel Sepúlveda Crespo
- Directores de la Tesis: José Luís Jiménez Fuentes (dir. tes.), Maria Angeles Muñoz Fernandez (dir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2016
- Idioma: inglés
- Tribunal Calificador de la Tesis: José María Almendral del Río (presid.), Pedro Lorenzo Majano Rodríguez (secret.), Blanca González Ortiz (voc.), María Francesca Ottaviani (voc.), Rafael Gómez Ramírez (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
The human immunodeficiency virus type 1(HIV-1)/hepatitis C virus (HCV) co-infection remains a growing and evolving epidemic, but new developments and enhanced models offer promising outcomes. Nanotechnology and specially dendrimers are considered emerging and exponential technologies with great potential to develop novel therapeutic and preventive strategies against HIV-1 and HCV infections due to similar sizes with biological structures.
The most common way to be infected with HIV-1 is through sexual exposure. In the absence of an effective vaccine, self-applied topical microbicides provide a female-controlled preventive option that not requires negotiation, consent or their partners knowing. Three percent of vaginally-applied G2-S16 microbicide, a polyanionic carbosilane dendrimer (PCD), in humanized BLT mice showed a good safety profile preventing the HIV-1 transmission at 84%. G2-S16 inhibited the HIV-1 infection at early stages by blocking the HIV-1 entry, particularly the gp120/CD4 interaction. G2-S16 inactivated HIV-1 particles by tight binding to HIV-1 envelope proteins provided a barrier to the infection for long periods and prevented the HIV-1 cell-to-cell transmission.
With the failure of clinical trials of the non-specific microbicides and that the use of single ARV as vaginal microbicides has not demonstrated to have a sufficient effect, more efforts to develop combinatorial approaches targeting entry and post-replication steps can be the best strategy to prevent the HIV-1 spread. Combinations based on G2-STE16/PCD (G2-S24P or G2-S16), G2-STE16/tenofovir (TFV) and G2-STE16/maraviroc (MRV) or PCD/PCD/PCD, PCD/PCD/TFV, PCD/PCD/MRV and PCD/TFV/MRV showed a synergistic activity profile and a reduction in EC50 against a broad-spectrum of HIV-1 isolates. These combinations maintained their potent anti-HIV-1 activity in the presence of acidic pH and seminal plasma and did not produce vaginal irritation after administration in a BALB/c mouse model.
Direct acting agents (DAA) have been successfully developed for the treatment of the chronic HCV infection. However, the lack of a HCV vaccine and the emergence of resistance makes of the development of novel agents an urgent need. By using an unbiased cell-based screening, we identified a family of seven PCD that inhibit the HCVcc infection. PCD inhibited early aspects of the HCV infection, interfered in the HCV entry against HCVpp and bona fide virions from different genotypes, had effect during viral adsorption and did not irreversibly alter the HCV virion infectivity with the exception of G2-S24P. G2-S24P was virucidal at high doses against the HCV infection. In summary, these results suggest that G2-S24P in combination with DAA can be effective antiviral agents, supporting further clinical research on these as potential therapies in the context of blocking the HCV transmission.
