T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice
Graduate School of Biomedical Sciences; Department of Medicine, Division of Diabetes; Immune Disease Institute and Department of Pediatrics
Medical Subject Headings
Animals; Antigens, CD7; Disease Models, Animal; Gene Expression; HIV Infections; HIV-1; Humans; Immunoglobulin Fragments; Immunoglobulin Variable Region; Leukocytes, Mononuclear; Mice; Mice, Inbred NOD; Mice, SCID; *RNA Interference; RNA, Small Interfering; RNA, Viral; T-Lymphocytes
Life Sciences | Medicine and Health Sciences
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.
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Citation: Cell. 2008 Aug 22;134(4):577-86. Epub 2008 Aug 7. Link to article on publisher's site
Kumar, Priti D.; Ban, Hong-Seok; Kim, Sang-Soo; Wu, Haoquan; Pearson, Todd; Greiner, Dale L.; Laouar, Amale; Yao, Jiahong; Haridas, Viraga; Habiro, Katsuyoshi; Yang, Yong-Guang; Jeong, Ji-Hoon; Lee, Kuen-Yong; Kim, Yong-Hee; Kim, Sung Wan; Peipp, Matthias; Fey, Georg H.; Manjunath, N.; Shultz, Leonard D.; Lee, Sang-Kyung; and Shankar, Premlata, "T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice" (2008). GSBS Student Publications. 1576.