Nanotechnology against HIV-1: safety and biodistribution of prophylactic microbicides and use as transfectants for a DC-based therapeutic vaccine

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 14-02-2020Esta tesis tiene embargado el acceso al texto completo hasta el 14-08-2021Human Immunodeficiency Virus (HIV) has been a challenging riddle for the scientific community and the health system since its discovery in 1984. According to UNAIDS data, almost 38 million people are currently living with HIV worldwide and only 23.3 have access to antiretroviral therapy (ART). Far from reaching the 2020 objectives, there is a prevention crisis, as the number of new infections decrease at a disturbing low rate, despite all the prophylactic methods available. Microbicides are rising as promising alternatives in response to the need of efficient, immediate and inconspicuous preventive methods, especially of women in developing countries. G2-S16 dendrimer is a microbicide designed for a topical application in the vagina and has been shown to be efficient in the prevention of HIV-1 infection. It is currently on the way to clinical trials. In this study, we test the safety of G2-S16 regarding its effect on the immune cells found in the female reproductive tract. The results showed that G2-S16 dendrimer does not modify TLR expression in epithelial cells, dendritic cells (DCs), macrophages (MΦs), or CD4+ T cells, nor does it affect their differentiation or activation of DCs, MΦs, CD4+ and CD8+ T cells, or B cells. In vivo studies in mice suggested that G2-S16 dendrimer is safe for vaginal and intravenous application, as it does not harm the vaginal epithelium, hematocrit, or structure and function of the organs studied (brain, heart, kidney, liver and spleen). HIV transmission correlates with unintended pregnancies, highlighting the health and social benefits of a gel of dual microbicide and contraceptive effect. We combined the contraceptive drug Platycodin D with G2-S16 and the results demonstrate that both compounds keep their effect in combination. Another scientific challenge in the fight against HIV is the finding of a functional cure. HIV is nowadays a chronic infection thanks to antiretroviral therapy, but it has issues like the appearing resistances, or lack of adhesion of the patients. A DC-based therapeutic vaccine would address these issues. We aimed to design a vaccine, testing two nanocompounds to transfect DCs with a HIV-derived peptide, maturing DCs in vitro, and studying their ability to stimulate a HIV-specific T and B cell immune response