TALENs Targeting HBV: Designer Endonuclease Therapies for Viral Infections

Abstract

Chronic viral infections have plagued humanity for millennia, causing lifelong and incurable diseases. For many viruses, persistence is caused by the presence of long-lived forms of viral DNA in infected cells. Current therapies can suppress viral replication, but they have little or no effect on long-lived DNA forms, and thus viral replication is able to resume as soon as therapy is stopped. This suggests that if long-lived DNA forms could be targeted therapeutically, cure might be possible (Figure 1). The recent development of designer targeted endonucleases such as homing endonucleases, zinc-finger nucleases (ZFNs), transcription activator–like effector nucleases (TALENs), and the CRISPR (clustered regularly interspaced short palindromic repeats) system has brought this idea closer to reality.1 The function of these enzymes is to specifically recognize and cleave selected DNA sequences, which results in gene disruption upon imprecise DNA repair. In this issue of Molecular Therapy, Bloom and colleagues investigate TALENs targeting the hepatitis B virus (HBV) genome and analyze their antiviral activity in several models of HBV infection, including an in vivo mouse model.2 Their detection of TALEN-induced mutations in the long-lived HBV covalently closed circular DNA (cccDNA) represents a substantial advance in the field and supports continued efforts to develop this approach for ultimate clinical use.