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Volume 8 Supplement 2

Frontiers of Retrovirology 2011

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Preclinical test of a lentivirus-mediated RNAi gene therapy against HIV-AIDS in the humanized mouse model


HIV-1 is still a major public health problem and one of the priorities of the World Health Organization. The development of HAART against HIV was a considerable advance for infected individuals, but this life-long treatment does only block virus replication, and no viral eradication is obtained. Furthermore, HAART may exhibit long-term toxicity and may eventually lead to the emergence of drug-resistant viral variants. We explore a new durable therapeutic intervention based on a gene therapy that induces RNA interference (RNAi) against HIV-1. In this pre-clinical research setting, "humanized" experimental mouse models are of interest considering the relative ease of handling and relatively low cost as compared to non-human primates.


We have developed an RNAi gene therapy based on the transduction of human hematopoietic progenitor cells (HPC) with lentiviral vectors encoding short-hairpin RNAs to induce silencing of HIV genes. We have tested the efficacy and safety of such a shRNA-based gene therapy strategy in the "Human Immune System" (HIS) BALB/c Rag2-/-IL-2Rγc-/- mouse model, which are reconstituted with human HPC that were first transduced ex vivo with a lentiviral vector expressing the antiviral shRNAs.


We observed a normal in vivo development of the human immune system with a good recovery of human shRNA+cells for the candidate shPol47, shPol1 and shRT5 inhibitors. However, the in vivo recovery of human shGag5-transduced cells was extremely poor, suggesting a negative impact of this specific shRNA on the development of the human immune system. When these 4 shRNAs were combined in a single lentiviral vector (R4), we observed a similar negative off-target effect due to the shGag5 component. Upon removal of shGag5 as in vector R3, transduction of human HPC results in a normal differentiation of the human immune system, highlighting the in vivo safety of this candidate R3 gene therapy vector for a clinical trial. Moreover, human HPC expressing the antiviral shNef generate human CD4+T cells with the ability to resist HIV-1 replication in a sequence specific manner.


Overall, these results underscore the usefulness of the HIS (BALB-Rag/γ) mouse model for testing the safety and efficacy of durable anti-HIV gene therapy approaches. In this model, human HPC expressing anti-HIV-1 shRNA give rise to multi-lineage reconstitution of the immune system in vivo and generate CD4+ T cells that are not susceptible for HIV-1 replication.

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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Centlivre, M., Legrand, N., Liu, YP. et al. Preclinical test of a lentivirus-mediated RNAi gene therapy against HIV-AIDS in the humanized mouse model. Retrovirology 8 (Suppl 2), P9 (2011).

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