Site-specific host gene modification by zinc finger nucleases: pointing the way to drug free control of HIV-1?

Abstract

Anti-retroviral therapy (ART) for human immunodeficiency virus-1 (HIV-1) infection has transformed its clinical course with spectacular reductions in morbidity and mortality, turning this once fatal diagnosis into a manageable chronic infection. However, ART has its limitations. Current ART does not eliminate the virus. Interruption of therapy results in rapid rebound of the virus, and such rebounds are associated with excess morbidity and mortality. This means that therapy once started is for life. This raises the issues of drug resistance due to suboptimal compliance, cumulative toxicities and mounting costs. Efforts to control the virus through novel interventions, particularly through cell or gene therapy have had a resurgence of interest as a single patient was apparently cured by an allogeneic stem cell transplantation from a donor who carried homozygous mutations that disable expression of the HIV-1 co-receptor CCR5. This paper reviews the state of play of gene therapy for HIV infection in the context of a recent paper showing the safety and feasibility of an approach that involves the ex vivo disruption of the ccr5 gene in autologous CD4 T cells using a virally delivered zinc finger nuclease, before their expansion and reinfusion. Although there are still considerable challenges, this approach may point towards a future drug free therapy for HIV-1 infection.