Date: 4th March 2020
The use of antiretroviral therapy (ART) has remarkably decreased the mortality and morbidity associated with HIV-1 infection, however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) is still increasing. Now scientists have formulated nanoparticles to deliver drugs across the blood-brain barrier to achieve HIV suppression.
HAND is partially due to the entry of HIV-1-infected monocytes into the brain. Once within the central nervous system (CNS) they differentiate into macrophages. These HIV-loaded macrophages are a major viral reservoir, providing a method for viral replication. This leads to other cell types becoming infected such as microganglia and astrocytes – through cellular dysfunction and apoptosis the subsequent toxicity causes clinical neurological dysfunction – the grade of which is related to the extent of macrophage activation.
The major hindrance to treating HAND is the inability of many traditional therapies to cross the BBB. In fact, ~25% of patients receiving ART, still develop one or more neurological syndromes.
A team led by Santosh Kumar, from the University of Tennessee Health Science Center, US, had previously used nanoparticles loaded with a commonly used antiretroviral, elvitegravir (EVG), to improve the uptake of EVG in monocyte-derived macrophages in vitro, and suppressed the virus in HIV-infected primary macrophages (Bone marrow-derived).
Now the team have tried a similar approach to determine whether it could be used as a potential tool for drug delivery to the brain, to enable crossing of the BBB and treatment of HIV-infected macrophages.
The research – published in Nature Communications – also tried to identify key molecular and clinical parameters including stability, biocompatibility, protein corona, and the cellular internalisation pathway of EVG nanoformulation for its potential clinical translation.
Conclusions and future applications:
Currently there is no specific treatment for HAND, as the BBB remains a problematic obstacle for systemic treatments to overcome. The work described here therefore may provide a novel therapeutic approach to eradicating the viral reservoir of HIV in the CNS. As a well established and FDA-approved integrase strand transfer inhibitor, EVG already has a favourable safety profile. In addition, with the safety and stability profiles of the PLGA-EVG NPs shown here, the data supports their potential use as a CNS delivery strategy.
We have seen recent advancements in BBB nanocarriers. The design of an enzyme delivery system, which encapsulated cargo in a nanoparticle, and targeted the brain was recently used in mice to support the treatment of Krabbe Disease. With the efforts made here in this paper, the toolbox we have to help bridge the BBB challenge is improving.
Just last week we also reported a next generation treatment that may support neurodegenerative diseases. In this case, Huntington’s Disease, where gene therapy was able to convert and reprogramme striatal astrocytes into neurons that could replace the diseased ‘faulty’ neurons..
In the future we may see a combination of therapies used together. Here, you can easily see the benefit of firstly depleting the viral reservoir of HIV-1 within the CNS by treating with PLGA-EVG NPs, then subsequently any damage that has already occurred could potentially be addressed by converting cells in vivo to replace those already damaged.
Although it should be noted that the study here whilst promising, is still in its infancy, the next step will be to test the technology in model animals in vivo. However, with technology moving so quickly, and many applications addressing different aspects of neurological dysfunction these once almost untreatable diseases are now within touching distance.
Gong, Y., P. Chowdhury, P. K. B. Nagesh, M. A. Rahman, K. Zhi, M. M. Yallapu and S. Kumar (2020). “Novel elvitegravir nanoformulation for drug delivery across the blood-brain barrier to achieve HIV-1 suppression in the CNS macrophages.” Scientific Reports 10(1): 3835.