Systemic administration of combinatorial dsiRNAs via nanoparticles efficiently suppresses HIV-1 infection in humanized mice.

Abstract

We evaluated the in vivo efficacy of structurally flexible, cationic PAMAM dendrimers as a small interfering RNA (siRNA) delivery system in a Rag2(-)/-γc-/- (RAG-hu) humanized mouse model for HIV-1 infection. HIV-infected humanized Rag2-/-γc-/- mice (RAG-hu) were injected intravenously (i.v.) with dendrimer-siRNA nanoparticles consisting of a cocktail of dicer substrate siRNAs (dsiRNAs) targeting both viral and cellular transcripts. We report in this study that the dendrimer-dsiRNA treatment suppressed HIV-1 infection by several orders of magnitude and protected against viral induced CD4(+) T-cell depletion. We also demonstrated that follow-up injections of the dendrimer-cocktailed dsiRNAs following viral rebound resulted in complete inhibition of HIV-1 titers. Biodistribution studies demonstrate that the dendrimer-dsiRNAs preferentially accumulate in peripheral blood mononuclear cells (PBMCs) and liver and do not exhibit any discernable toxicity. These data demonstrate for the first time efficacious combinatorial delivery of anti-host and -viral siRNAs for HIV-1 treatment in vivo. The dendrimer delivery approach therefore represents a promising method for systemic delivery of combinations of siRNAs for treatment of HIV-1 infection.

• Authors: Jiehua Zhou, C Preston Neff, Xiaoxuan Liu, Jane Zhang, Haitang Li, David D Smith, Piotr Swiderski, Tawfik Aboellail, Yuanyu Huang, Quan Du, Zicai Liang, Ling Peng, Ramesh Akkina, John J Rossi
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 12 Pg. 2228-38 (Dec 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21952167 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Dendrimers
• Interleukin Receptor Common gamma Subunit
• RNA, Small Interfering
• RNA, Viral
• Rag2 protein, mouse
• rev Gene Products, Human Immunodeficiency Virus
• rev protein, Human Immunodeficiency Virus-1
• tat Gene Products, Human Immunodeficiency Virus
• DICER1 protein, human
• Ribonuclease III
• DEAD-box RNA Helicases

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, virology)
• DEAD-box RNA Helicases (metabolism)
• DNA-Binding Proteins (physiology)
• Dendrimers
• Disease Models, Animal
• Flow Cytometry
• HIV Infections (genetics, prevention & control, virology)
• HIV-1 (physiology)
• Humans
• Interleukin Receptor Common gamma Subunit (physiology)
• Leukocytes, Mononuclear (cytology, metabolism, virology)
• Liver (cytology, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Nanoparticles (administration & dosage)
• RNA, Small Interfering (administration & dosage, genetics)
• RNA, Viral (genetics)
• Ribonuclease III (metabolism)
• T-Lymphocytes, Helper-Inducer (immunology, virology)
• Viral Load
• Viremia (genetics, prevention & control, virology)
• rev Gene Products, Human Immunodeficiency Virus (antagonists & inhibitors, genetics, metabolism)
• tat Gene Products, Human Immunodeficiency Virus (antagonists & inhibitors, genetics, metabolism)