Abstract
We previously reported that activation of the host autophagic protein, Beclin1, by HIV-1 infection represents an essential mechanism in controlling HIV replication and viral-induced inflammatory responses in microglial cells. Existing antiretroviral therapeutic approaches have been limited in their ability to cross the blood-brain barrier effectively and recognize and selectively eliminate persistent HIV-infected brain reservoirs. In the present study and for the first time, the bio-distribution and efficacy of noninvasive intranasal delivery of small interfering RNA (siRNA) against the Beclin1 gene using the cationic linear polyethylenimines (PEI) as a gene carrier was investigated in adult mouse brain. Fluorescein isothiocyanate (FITC)-labeled control siRNA delivered intranasally was found in the cytoplasm of neurons and glial cells of the prefrontal cortex at 4 and 24 hours post-delivery, with no major adverse immune reaction encountered. Intranasal delivery of the siRNA targeting Beclin1 significantly depleted the target protein expression levels in brain tissues with no evidence of toxicity. Binding of siRNA to PEI-polymer was characterized and confirmed by Raman spectroscopy. These results indicate that the intranasal drug delivery allows for the direct delivery of the PEI-siRNA nano-complex to the central nervous system, which could potentially offer an efficient means of gene silencing-mediated therapy in the HIV-infected brain.
Highlights
We previously reported that activation of the host autophagic protein, Beclin[1], by human immunodeficiency virus (HIV)-1 infection represents an essential mechanism in controlling HIV replication and viral-induced inflammatory responses in microglial cells
In spite of a dramatic reduction in human immunodeficiency virus (HIV)-associated dementia (HAD), HIV RNA copy number and great improvement in the survival rate among people living with HIV using long-term combined anti-retroviral therapy, virus persistence continues in latent virus reservoirs and the virus can re-populate once cART is discontinued [Reviewed in ref.[1]
We have discovered that activation of the host autophagic pathway by HIV-1 infection represents an essential mechanism in controlling viral replication and viral-induced inflammatory responses in microglial cells[28]
Summary
We previously reported that activation of the host autophagic protein, Beclin[1], by HIV-1 infection represents an essential mechanism in controlling HIV replication and viral-induced inflammatory responses in microglial cells. Binding of siRNA to PEI-polymer was characterized and confirmed by Raman spectroscopy These results indicate that the intranasal drug delivery allows for the direct delivery of the PEI-siRNA nanocomplex to the central nervous system, which could potentially offer an efficient means of gene silencing-mediated therapy in the HIV-infected brain. CART is not totally effective in controlling HIV replication in brain cells and does not directly target the inflammatory cascades which are believed to be the primary cause of neuronal injury or dysfunction related to HAD pathology[2,3,4,5] Despite their instability and potential to induce insertion mutagenesis, toxicity, and immunogenicity, in recent years the use of RNA interference (RNAi)-based therapeutics such as small interfering (si)/short hairpin (sh) RNAs to mediate silencing of gene expression has shown exciting prospects for the development of novel therapeutic strategies[6]. Our data shows optimization of the efficacy of siBeclin[1] in attenuating HIV replication and HIV-induced inflammatory responses in vitro for in vivo use, the feasibility of using PEI reagent as gene carrier, and the bio-distribution of the nano-complex in brain via intranasal delivery
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
