A new study has used exosomes to deliver novel proteins into the cells of HIV infected mice to prevent the virus from replicating. This study has the potential to pave the way for the development of an exome-mediated delivery platform to achieve epigenetic repression of HIV.
Human Immunodeficiency Virus
Human Immunodeficiency Virus-1 (HIV-1) is the most common pathogenic strain of human immunodeficiency virus. HIV-1 attacks the immune system by infecting CD4+ cells, which are a type of white blood cell that are vital for fighting off infection. Without treatment, HIV destroys these white blood cells, reducing the body’s ability to mount an immune response. This eventually results in the development of acquired immune deficiency syndrome (AIDS).
The pursuit for new HIV therapies is challenging for a number of reasons. One reason is that HIV can enter a dormant-like state. In this state, the virus can evade treatments, only to reactivate at a later date. It is particularly difficult when the virus hides in the brain as the blood-brain barrier often prevents treatments from entering into those tissues.
With the failure of the recent HIV-1 vaccine trial and the inefficiencies associated with combination antiretroviral therapy, such as the development of drug resistance, adverse effects, and poor central nervous system penetration, there is an ever-pressing need to re-evaluate the strategies to combat HIV.
Epigenetic repression of HIV – a ‘block and lock’ strategy
It has been hypothesised that a safer therapy could be deliverable in vivo and target the stable epigenetic repression of the virus. This in turn would induce a stable ‘block and lock’ of virus expression. Overall, this approach aims to block the virus’ ability to replicate and lock it in its dormant state.
In order to minimise treatment toxicity, the researchers behind this study, published in Nature Communications, reasoned that epigenetic proteins, such as DNA Methyl Transferase 3 A (DNMT3A), could be used to down-regulate HIV-1 transcription.
Hypermethylation of the viral 5’ long terminal repeat (LTR) has previously been reported to cause latency in cell models of HIV infection, as well as in some long-term ART-treated individuals. Therefore, the authors reasoned that targeted DNA methylation of the 5’ LTR could represent a promising avenue for a ‘block and lock’ strategy as their method would silence HIV replication.
Using exosomes to deliver epigenetic repression of HIV
Exosomes offer an approach whereby specific therapeutic moieties can be packaged into discreet, pervasive, nanosized particles. An advantage of using exosomes to deliver therapeutics is that they are well tolerated by the immune system. In this recent study, the researchers used exosomes in their approach to cross the blood brain barrier and deliver treatments to the brain.
The exosomes used contained a novel recombinant anti-HIV protein, called ZPAMt. The ZPAMt protein was designed to attach to the LTR region that is essential for virus replication. The protein has an epigenetic marker in it that changes the way the virus’ genetic information is expressed. It works by suppressing the expression of the genetic information, thus making the virus unable to divide and multiply.
When the researchers administered their exosome-based treatment to mice infected with HIV, they found that the exosome-delivered protein was capable of silencing the HIV-infected cells. Moreover, the HIV infected mice showed suppression of HIV expression in the bone marrow, spleen and brain.
Future directions
Overall, these findings demonstrate that exosomes can be used to deliver proteins into infected cells in the body, including the brain, to silence HIV replication. In the future, the researchers hope to continue their work by using exosomes to deliver gene-excision machinery capable of cutting the HIV out of the genome of infected people. Additionally, this innovative technology could also be used as a future delivery method for various other diseases of the brain, such as Parkinson’s and Alzheimer’s.
