Chemokine receptor 5 knockout strategies.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA. pcannon@usc.edu
Paula
P
Cannon
Carl
C
June
D019264:Adoptive Transfer; D000818:Animals; D065100:CCR5 Receptor Antagonists; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D015658:HIV Infections / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D013601:T-Lymphocytes / Q000821:virology; D053586:Virus Internalization
D065100:CCR5 Receptor Antagonists
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