Related Experiment Video
Updated: Jul 13, 2026
Humanized NOG Mice for Intravaginal HIV Exposure and Treatment of HIV Infection
Published on: January 31, 2020
Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates
Dong Sung An1, Robert E Donahue, Masakazu Kamata
1Department of Hematology and Oncology, AIDS Institute, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Abstract:
RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.
Insights
Stable expression of small interfering RNAs (siRNAs) targeting chemokine receptor 5 (CCR5) was achieved in primates via stem cell transplant. This gene silencing approach shows potential for treating HIV-1 and other blood diseases.
Area of Science:
- Molecular Biology
- Gene Therapy
- Immunology
Background:
- RNA interference (RNAi) is a gene silencing mechanism with therapeutic potential.
- Endogenous RNAi is vital for cellular functions, necessitating safe siRNA delivery and expression.
- Chemokine (c-c motif) receptor 5 (CCR5) is a key co-receptor for HIV-1 entry.
Purpose of the Study:
- To assess the stable expression of siRNAs targeting CCR5 in primates.
- To evaluate the safety and efficacy of siRNA delivery via hematopoietic stem cell transplant.
- To determine the impact of CCR5 downregulation on susceptibility to simian immunodeficiency virus (SIV).
Main Methods:
- CD34+ hematopoietic stem/progenitor cells were engineered to express siRNAs targeting CCR5.
- These modified cells were transplanted into primates.
- Hematopoietic reconstitution and gene expression were monitored post-transplant.
- Lymphocyte susceptibility to SIV infection was assessed ex vivo.
Main Results:
- Stable expression of CCR5-directed siRNAs was observed in primates 14 months post-transplant.
- Consistent downregulation of CCR5 expression was achieved in marked lymphocytes.
- Engineered lymphocytes exhibited reduced susceptibility to SIV infection ex vivo.
Conclusions:
- Hematopoietic stem cell transplant can facilitate stable siRNA expression in primates.
- This approach offers a potential strategy for gene therapy of blood diseases like HIV-1.
- siRNA-mediated CCR5 downregulation is a viable method for enhancing resistance to viral infection.
