T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice

Abstract

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 novel delivery method in humanized mice, 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 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+ PBMC. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naïve 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.

Special delivery: targeted therapy with small RNAs

“…Systemic injection of the CD7 scFv-9 amino acid poly-(D)-arginine peptide, complexed with siRNAs directed against CCR5 (a chemokine receptor that is an HIV coreceptor) and HIV vif and tat, suppresses HIV infection in humanized mice without inducing toxicity. 54 A similar approach can be used to suppress dengue virus infection in vitro in monocyte-derived dendritic cells using DC3-9 amino acid poly-(D)-arginine peptide for delivering siRNAs to suppress expression of dengue genes or TNF-a, which has a major role in dengue pathogenesis. These complexes also suppress TNF-a production induced by innate immune stimulation of dendritic cells in vivo.…”

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

“…19 PG16 was identified in secreted culture supernatants of memory B cells from a clade A HIV-1-infected subject and binds to quaternary epitopes on the V1V2 loops of gp120. 20 We show here that a single intramuscular injection of these FG ADV5 viral particles (VPs) produced high serum titers of bNAb in Hu-PBL humanized mice 21 and protected against HIV-1 infection, despite multiple repeated intraperitoneal challenge with HIV-1.…”

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

“…Oh and colleagues [66] have shown that the aminopeptidase P antibody specifically targeted nanoparticles to the caveolae of rat lung endothelium, thus providing a novel targeting delivery system for siRNA. On the other hand, Kumar et al [67] reported the T cell specific delivery of anti-HIV siRNA in a mouse model.…”

“…Treatment with siRNA conjugated to a peptide and an anti-CD7 antibody ensured selected delivery of the siRNA and led to suppression of the virus and prevention of the loss of CD4 T cells [67] .…”