title: T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice.
abstract: Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD7-9R) for T cell-specific siRNA delivery in NOD/SCIDIL2rgamma-/- mice reconstituted with human lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model.
authors.affiliation: Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Priti
authors.initials: P
authors.lastname: Kumar
authors.forename: Hong-Seok
authors.initials: HS
authors.lastname: Ban
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Haoquan
authors.initials: H
authors.lastname: Wu
authors.forename: Todd
authors.initials: T
authors.lastname: Pearson
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Amale
authors.initials: A
authors.lastname: Laouar
authors.forename: Jiahong
authors.initials: J
authors.lastname: Yao
authors.forename: Viraga
authors.initials: V
authors.lastname: Haridas
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Habiro
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Yang
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Kuen-Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.forename: Georg H
authors.initials: GH
authors.lastname: Fey
authors.forename: N
authors.initials: N
authors.lastname: Manjunath
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Sang-Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Premlata
authors.initials: P
authors.lastname: Shankar
mesh_terms: D000818:Animals; D019011:Antigens, CD7 / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics* / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D019011:Antigens, CD7; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D034741:RNA, Small Interfering; D012367:RNA, Viral