Journal
CELL
Volume 134, Issue 4, Pages 577-586Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.06.034
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Funding
- NIH/National Institute of Allergy and Infectious Diseases [RO1 A1071882, R21 AI06532, AI075419]
- Korea Ministry of Education and Science Technology [R01-2006-000-10506-0, F104AA010005-07A0101-00510]
- Seoul RBD [CR070027]
- CFAR [P30 A060354]
- NIH [CA34196]
- Juvenile Diabetes Research Foundation
- MOEHRD [KRF-2006-352-D00070]
- Wilhelm Sander Foundation
- National Research Foundation of Korea [R01-2006-000-10506-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 (scFvCD79R) for T cell-specific siRNA delivery in NOD/SCIDIL2r gamma(-/-) 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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