[HTML][HTML] T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice

P Kumar, HS Ban, SS Kim, H Wu, T Pearson… - Cell, 2008 - cell.com
P Kumar, HS Ban, SS Kim, H Wu, T Pearson, DL Greiner, A Laouar, J Yao, V Haridas…
Cell, 2008cell.com
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/SCIDIL2rγ−/− mice reconstituted with human
lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu …
Summary
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/SCIDIL2rγ−/− 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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