title: Phenotypic knockout of HIV type 1 chemokine coreceptor CCR-5 by intrakines as potential therapeutic approach for HIV-1 infection.
abstract: A genetic defect in a CC-chemokine receptor (CCR)-5, the principal coreceptor for the macrophage-tropic HIV type 1 (HIV-1), recently was found to naturally protect CCR-5-defective, but healthy, individuals from HIV-1 infection. In this study, we mimic the natural resistance of the CCR-5-defective individuals by designing a strategy to phenotypically knock out CCR-5. The inactivation of the CCR-5 coreceptor is accomplished by targeting a modified CC-chemokine to the endoplasmic reticulum to block the surface expression of newly synthesized CCR-5. The lymphocytes transduced to express the intracellular chemokine, termed "intrakine," were found to be viable and resistant to macrophage-tropic HIV-1 infection. Thus, this gene-based intrakine strategy targeted at the conserved cellular receptor for the prevention of HIV-1 entry should have significant advantages over currently described approaches for HIV-1 therapy.
authors.affiliation: Department of Cancer Biology, Comprehensive Cancer Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Yang
authors.forename: X
authors.initials: X
authors.lastname: Bai
authors.forename: X F
authors.initials: XF
authors.lastname: Huang
authors.forename: C
authors.initials: C
authors.lastname: Yao
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000628:therapy*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D019556:COS Cells; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000502:physiology; D015316:Genetic Therapy; D015726:Giant Cells; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000502:physiology; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D016324:Sequence Tagged Sites; D014162:Transfection; D014779:Virus Replication
chemical_list: D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D011994:Recombinant Proteins