Therapeutic applications of dendritic nanosystems against viral infections: Human Immunodeficiency Virus Type 1, Herpes Simplex Virus Type 2 and Human Cytomegalovirus
Title (trans.)
Aplicaciones terapéuticas de sistemas dendríticos frente a infecciones virales: Virus de la Inmunodeficiencia Humana Tipo 1, Virus el Herpes Simple Tipo 2 y Citomegalovirus HumanoAuthor
Royo Rubio, ElenaEntity
UAM. Departamento de Biología Molecular; Hospital General Universitario Gregorio MarañónDate
2022-10-21Subjects
Inmunodeficiencia; Nanotecnología--Aplicaciones científicas; Dendritas--Aplicaciones científicas; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 21-10-2022
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
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
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