Purpose of review: Individuals homozygous for a deletion in the chemokine receptor 5 (CCR5) gene (CCR5Δ32) are almost completely resistant to HIV-1 infection. A recent report that transplantation of hematopoietic stem or progenitor cells (HSCs) from a CCR5Δ32 homozygous donor effectively cured an HIV patient has increased interest in the development of strategies that could be used to recreate this phenotype using a patient's own cells. This review will focus on recent developments to disrupt CCR5 expression in both autologous T cells and HSCs.
Recent findings: CCR5 expression in HIV-1 target cells can be suppressed by RNA-based gene suppression technologies such as RNA interference, or completely eliminated by zinc finger nuclease (ZFN)-mediated gene disruption. ZFNs bind specifically to a DNA sequence and generate a double-stranded DNA break, whose subsequent repair by the cell's error-prone nonhomologous end-joining pathway can lead to permanent disruption of the gene's open reading frame. Recent developments in humanized mouse models have facilitated preclinical studies that have demonstrated the ability of CCR5-targeted ZFNs to suppress HIV-1 in vivo, when used to modify human T cells or HSCs. The same CCR5 ZFNs are now being evaluated in a phase I clinical trial of ex vivo expanded autologous T cells.
Summary: CCR5 gene knockout in T cells or HSCs by ZFNs effectively suppresses the replication of CCR5-tropic strains of HIV-1 in animal models. ZFNs are currently being evaluated in a phase I clinical trials using ex vivo expanded T cells and HSCs targeted therapies are under development.