Therapeutic applications of dendritic nanosystems against viral infections: Human Immunodeficiency Virus Type 1, Herpes Simplex Virus Type 2 and Human Cytomegalovirus

Abstract

Despite being the cause of epidemics for thousands of years, the study of viruses is relatively young. However, the appearance of previously unknown viruses and the spread of already known viruses in new areas have led to a massive increase in virology research. Refined approaches in the study of viruses have allowed for an in depth understanding of the molecular, evolutionary, and epidemiological aspects of viruses, which has reduced the mortality and morbidity of these infectious diseases. Nevertheless, viral infections remain one of the major global health problems, mostly in vulnerable populations such as immunocompromised patients and people from developing countries. To illustrate, the global population living with Human Immunodeficiency Virus-1 (HIV-1) exceeds 37 million people and each year there are more than 1,5 million new infections. Another sexually transmitted viral pathogen is Herpes Simplex Virus-2 (HSV-2), the causative agent of more than 490 million infections around the world. However, sexual transmission is not the only way by which viral pathogens are widely disseminated, for example Human Cytomegalovirus (HCMV), which affects more than 50% of the global population and reaches values of more than 90% in some regions, is mostly acquired during childhood or through organ transplant or blood transfusion. There are currently different therapies for diseases produced by these three viruses, but there is no definitive cure and treatments face diverse challenges such as timely diagnosis, access and adherence to treatment or appearance of resistances. In this scenario, nanotechnology presents itself as a promising tool for the development of new antiviral therapies. In this work, novel PEGylated cationic carbosilane dendrimers (PCCDs) have demonstrated to be efficient for viral inhibition in two different approaches: their use as delivery vehicles and their antiviral activity per se. In the first approach, the use as delivery systems, these dendrimers have proven to be biocompatible and effectively delivered into target cells. In addition, they have proved to form stable complexes with miRNAs that present anti-HIV-1 activity, which significantly and specifically improved the inhibition capacity of these RNA molecules by themselves. In the second approach, the antiviral activity per se, PCCDs have shown to effectively inhibit the attachment of viral glycoproteins from HSV-2 and HCMV to heparan sulphate proteoglycans, thus preventing the infection of target cells. Both therapeutic strategies have demonstrated that G2-SN15-PEG and G3-SN31-PEG dendrimers are promising candidates to be used against Retroviridae and Herpesviridae infections. Last part of this work consisted in the study of the application of micellar carbosilane dendrons in the development of a dendritic cell (DC)-based therapeutic vaccine for HIV-1. Dendrimicelles were shown to be valid carriers of HIV-1-derived peptides into moDCs, which induced them to a slight maturation. Experiments with T and B cell activation and release of inflammatory cytokines confirmed a slight stimulation of HIVspecific immune response. Collectively, these experiments confirmed that EG3SO3Na, ChG3SO3Na, EG3NMe3I, and ChG3NMe3I dendrimicelles are valid candidates to be used in the development of a therapeutic vaccine against HIV-1