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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / virology*
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DEAD-box RNA Helicases / metabolism
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DNA-Binding Proteins / physiology
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Dendrimers
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Disease Models, Animal
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Flow Cytometry
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HIV Infections / genetics
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HIV Infections / prevention & control*
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HIV Infections / virology*
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HIV-1 / physiology*
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Humans
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Interleukin Receptor Common gamma Subunit / physiology
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / metabolism
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Leukocytes, Mononuclear / virology
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Liver / cytology
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Liver / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Nanoparticles / administration & dosage*
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RNA, Small Interfering / administration & dosage*
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RNA, Small Interfering / genetics
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RNA, Viral / genetics
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Ribonuclease III / metabolism
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / virology
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Viral Load
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Viremia / genetics
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Viremia / prevention & control
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Viremia / virology
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rev Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors
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rev Gene Products, Human Immunodeficiency Virus / genetics
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rev Gene Products, Human Immunodeficiency Virus / metabolism
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tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors
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tat Gene Products, Human Immunodeficiency Virus / genetics
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tat Gene Products, Human Immunodeficiency Virus / metabolism
Substances
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DNA-Binding Proteins
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Dendrimers
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Interleukin Receptor Common gamma Subunit
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RNA, Small Interfering
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RNA, Viral
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Rag2 protein, mouse
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rev Gene Products, Human Immunodeficiency Virus
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rev protein, Human Immunodeficiency Virus-1
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tat Gene Products, Human Immunodeficiency Virus
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DICER1 protein, human
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Ribonuclease III
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DEAD-box RNA Helicases