title: Role of CXCR4 internalization in the anti-HIV activity of stromal cell-derived factor-1α probed by a novel synthetically and modularly modified-chemokine analog.
abstract: The natural ligands of two major human immunodeficiency virus type 1 (HIV-1) co-receptors, CXCR4 and CCR5, can profoundly inhibit the replication of HIV-1 that uses these co-receptors for entry into the target cells. It has been postulated that these natural chemokines inhibit HIV-1 infection by blocking common binding sites on CXCR4 or CCR5 that are required for HIV-1 envelope glycoprotein gp120 interaction with its co-receptor and/or by inducing receptor internalization. To investigate whether receptor internalization caused by stromal cell-derived factor (SDF)-1α, a natural ligand of CXCR4, plays a role in its anti-HIV activity, we applied the SMM (synthetically and modularly modified)-chemokine approach to generate a functional probe of SDF-1α that retains significant CXCR4 binding but does not induce CXCR4 internalization. The antiviral study of this functional probe analog versus wild-type SDF-1α showed that, despite the significant CXCR4 binding activity, this probe analog displayed a complete loss of effect in causing CXCR4 internalization and greatly diminished antiviral activity. Interestingly, this new analog also showed a decreased number of overlapping binding sites with HIV-1 on CXCR4 transmembrane and extracellular domains. The correlation of the decrease in the anti-HIV activity with the loss of CXCR4 internalization observed with this probe molecule suggests that receptor internalization may play an important role in the anti-HIV activity of SDF-1α and possibly other natural chemokines. This further implies that any modifications in SDF-1α that result in a reduction or loss of internalization activity may result in analogs that are not suitable as effective HIV-1 inhibitors that target CXCR4, unless such modifications also result in improved CXCR4 interaction with increased number of overlapping binding sites with HIV-1, thus leading to more effective steric hindrance against HIV-1.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Chang-Zhi
authors.initials: CZ
authors.lastname: Dong
authors.forename: Shaomin
authors.initials: S
authors.lastname: Tian
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Won-Tak
authors.initials: WT
authors.lastname: Choi
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: An
mesh_terms: D001667:Binding, Competitive; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism*; D057809:HEK293 Cells; D023581:HIV Fusion Inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008024:Ligands; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D053585:Virus Attachment
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D023581:HIV Fusion Inhibitors; D008024:Ligands; D019713:Receptors, CCR5; D019718:Receptors, CXCR4
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