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

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.

Insights into RNA Interference as Antiviral Defense

“…The siRNA even delivered in vivo in infected animals inhibited Japanese encephalitis virus in mice, HBV and influenza virus in transgenic mice [44][45][46]. The HIV-1 core as well as accessory proteins and several essential host genes used as RNAi target for HIV-1 inhibition in vivo using humanized mice infected with HIV-1.…”

Chronic hepatitis B: Are we close to a cure?

“…The most intriguing approaches in this field involve epigenetic modifications [29]. Furthermore, RNA interference (RNAi) has been shown to potently block viral mRNA [30,31]. However, the possibility of translating these proofs of concept into the clinical arena currently is still distant.…”

Hepatitis B: Working Towards a Cure

“…In multiple mouse studies, small interfering RNA (siRNA) has been shown to significantly reduce expression of HBsAg and HBeAg in the liver, decrease both HBV RNA and DNA levels, and reduce HBV cccDNA in the liver [36,38]. Studies are ongoing to determine the best mode of delivery of the siRNAs, with some groups finding success using RNAi-activating lentiviruses [39].…”