Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

Bloom, Kristie; Maepa, Mohube Betty; Ely, Abdullah; Arbuthnot, Patrick

Further evaluation of gene therapy-based immune modulation explored antiviral effects of sequences encoding interleukins. Crettaz et al. assessed efficacy of HDAd-delivered interleukin-12 (IL-12) in the WHV model [98] . The authors used a murine IL-12 sequence, under transcriptional control of an inducible promoter, and delivered the cassette directly to the liver with the viral vector. Interestingly, woodchucks with a viral load lower than 10 10 viral genome equivalents per ml of serum responded well to treatment, whereas those with higher viral loads did not. Extensive characterization revealed decreased intrahepatic viral DNA and RNA levels. Liver inflammation was reduced, and woodchuck hepatitis e and surface antigens were cleared from the serum. Significantly, disappearance of intrahepatic core antigen was attributed to a T-cell response against the virus, which was induced by IFN-γ. Importantly, the treatment was shown to be well-tolerated. The same group subsequently evaluated efficacy of IL-12 expressed from a Semliki Forest Virus vector [99] . While the aim was to assess the anti-tumor effects of the constructs in WHV-induced HCC, the authors also showed strong antiviral responses resulting from intrahepatic IL-12 expression. As before, the anti-tumor and antiviral effects were attributed to the induction of T-cell responses. The potential of using cytokines to treat HBV infection was further highlighted by a recent study that evaluated efficacy of dual expression of IFN-α and IL-15 to counter HBV replication in transgenic mice [100] . Co-administration of an AAV encoding the IFN-α gene and an AAV carrying the IL-15 sequence resulted in near complete clearance of intrahepatic HBc and viral DNA replication intermediates. More importantly, IFN-α and IL-15 expression were shown to induce an antibody response and a functional antiviral CD8 + T-cell response. The authors further assessed their combination strategy using recombinant IFN-α and IL-15 on samples from patients with chronic HBV infection. After stimulation of peripheral blood mononuclear cells from these patients with an HBc peptide in the presence of IFN-α and IL-15, effector function was restored to HBV specific CD8 + T-cells.