title: 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.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, City of Hope, Duarte, California 91010, USA.
authors.forename: Jiehua
authors.initials: J
authors.lastname: Zhou
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Liu
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.forename: Haitang
authors.initials: H
authors.lastname: Li
authors.forename: David D
authors.initials: DD
authors.lastname: Smith
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: Tawfik
authors.initials: T
authors.lastname: Aboellail
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Huang
authors.forename: Quan
authors.initials: Q
authors.lastname: Du
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.forename: Ling
authors.initials: L
authors.lastname: Peng
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D050091:Dendrimers; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015658:HIV Infections / Q000235:genetics / Q000517:prevention & control* / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D043244:Ribonuclease III / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014766:Viremia / Q000235:genetics / Q000517:prevention & control / Q000821:virology; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050091:Dendrimers; D053631:Interleukin Receptor Common gamma Subunit; D034741:RNA, Small Interfering; D012367:RNA, Viral; C499308:Rag2 protein, mouse; D054321:rev Gene Products, Human Immunodeficiency Virus; C514860:rev protein, Human Immunodeficiency Virus-1; D054322:tat Gene Products, Human Immunodeficiency Virus; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases