Title

T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice.

Document Type

Article

Publication Date

2008

Keywords

Antigens-CD7, Disease-Models-Animal, Gene-Expression, HIV-Infections, HIV-1, Humans, Immunoglobulin-Fragments, Immunoglobulin-Variable-Region, Leukocytes-Mononuclear, Mice-Inbred-NOD, Mice-SCID, RNA-Interference, RNA-Small-Interfering, RNA-Viral, T-Lymphocytes

JAX Source

Cell 2008 Aug; 134(4):577-86.

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.