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.
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.
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.
aMolecular Microbiology & Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Correspondence to Associate Professor Paula Cannon, PhD, Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine 2011 Zonal Avenue, HMR502 Los Angeles, CA 90033, USA Tel: +1 323 442 1510; e-mail: email@example.com