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Sustained inhibition of hepatitis B virus replication in vivo using RNAi-activating lentiviruses

Gene Therapy volume 22, pages 163–171 (2015)Cite this article

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Abstract

Chronic infection with hepatitis B virus (HBV) puts individuals at high risk for complicating cirrhosis and liver cancer, but available treatment to counter the virus rarely eliminates infection. Although harnessing RNA interference (RNAi) to silence HBV genes has shown the potential, achieving efficient and durable silencing of viral genes remains an important goal. Here we report on the propagation of lentiviral vectors (LVs) that successfully deliver HBV-targeting RNAi activators to liver cells. Mono- and tricistronic artificial primary microRNAs (pri-miRs) derived from pri-miR-31, placed under transcriptional control of the liver-specific modified murine transthyretin (mTTR) promoter, caused efficient inhibition of HBV replication markers. The tricistronic cassette was capable of silencing a mutant viral target and the effects were observed without disrupting the function of an endogenous miR (miR-16). The mTTR promoter stably expressed a reporter transgene in mouse livers over a study period of 1 year. Good silencing of HBV genes, without evidence of toxicity, was demonstrated following intravenous injection of LVs into neonatal HBV transgenic mice. Collectively, these data indicate that LVs may achieve sustained inhibition of HBV replication that is appealing for their therapeutic use.

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Acknowledgements

We are grateful to National Health Laboratory Services, Johannesburg for assistance with measurement of ALT activities. Financial assistance was received from the South African National Research Foundation (NRF, GUNs 81768, 81692, 68339, 85981 and 77954), Medical Research Council, Poliomyelitis Research Foundation, Stella and Paul Loewenstein Charitable and Educational Trust, German Academic Exchange Service (DAAD). Advice and practical assistance from Drs Tuan Nguyen and Dina Kremsdorf is gratefully acknowledged.

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  1. Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa

    D Ivacik, A Ely & P Arbuthnot

  2. Agence Nationale de Sécurité du Médicament et des produits de Santé, Saint Denis, France

    N Ferry

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Ivacik, D., Ely, A., Ferry, N. et al. Sustained inhibition of hepatitis B virus replication in vivo using RNAi-activating lentiviruses. Gene Ther 22, 163–171 (2015). https://doi.org/10.1038/gt.2014.94

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