Migration ofAntigen-Specific T Cells Away from CXCR4-Binding Human ImmunodeficiencyVirus Type 1gp120

Abstract

Cell-mediated immunity depends in part on appropriate migration and localization of cytotoxic T lymphocytes (CTL), a process regulated by chemokines and adhesion molecules. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode chemotactically active proteins, suggesting that dysregulation of immune cell trafficking may be a strategy for immune evasion. HIV-1 gp120, a retroviral envelope protein, has been shown to act as a T-cell chemoattractant via binding to the chemokine receptor and HIV-1 coreceptor CXCR4. We have previously shown that T cells move away from the chemokine stromal cell-derived factor 1 (SDF-1) in a concentration-dependent and CXCR4 receptor-mediated manner. Here, we demonstrate that CXCR4-binding HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific CTL, away from high concentrations of the viral protein. This migratory response is CD4 independent and inhibited by anti-CXCR4 antibodies and pertussis toxin. Additionally, the expression of X4 gp120 by target cells reduces CTL efficacy in an in vitro system designed to account for the effect of cell migration on the ability of CTL to kill their target cells. Recombinant X4 gp120 also significantly reduced antigen-specific T-cell infiltration at a site of antigen challenge in vivo. The repellant activity of HIV-1 gp120 on immune cells in vitro and in vivo was shown to be dependent on the V2 and V3 loops of HIV-1 gp120. These data suggest that the active movement of T cells away from CXCR4-binding HIV-1 gp120, which we previously termed fugetaxis, may provide a novel mechanism by which HIV-1 evades challenge by immune effector cells in vivo.

Human Immunodeficiency Virus Type 1 Envelope gp120 Induces a Stop Signal and Virological Synapse Formation in Noninfected CD4+T Cells

“…HIV-1 gp120 has also been shown to act like a chemoattractant and influence T-cell migration in CD4-dependent and CD4-independent manners. However, the stopping effect reported here is distinct from the chemotactic capacity of cell-free HIV-1 or simian immunodeficiency virus and soluble virus envelope proteins to attract CD4 ϩ T cells or CD8 ϩ T cells (4,31,32). It also differs from the CXCR4-mediated repelling effect of high concentrations of soluble HIV-1 gp120 on CD8 ϩ T cells (4).…”

X4 Human Immunodeficiency Virus Type 1 gp120 Down-Modulates Expression and Immunogenicity of Codelivered Antigens

“…HIV-1 gp120 is able to directly interact with chemokine receptors; for example, X4-gp120 has been shown to mediate signaling in murine and rat cells (3,11,28). Although there are no specific reports that indicate that R5 HIV-1 gp120 can trigger murine CCR5, this protein has been shown to bind this chemokine receptor on rat cells (20).…”

Murine B16 Melanomas Expressing High Levels of the Chemokine Stromal-Derived Factor-1/CXCL12 Induce Tumor-Specific T Cell Chemorepulsion and Escape from Immune Control

“…CM, 10-or 20-fold concentrated, undiluted or diluted 1/10 in DMEM containing 0.5% FCS, was added in the lower, upper, or both lower and upper chambers of the Transwell to generate a standard "checkerboard" analysis of cell migration including measurements of chemotaxis, fugetaxis, and chemokinesis (3,5,9,10). Further control wells assessed the chemotactic, fugetactic, and chemokinetic activity of rCXCL12 at concentrations from 10 ng/ml to 1 g/ ml.…”

“…Cytotoxicity of OT-1 CD8 ϩ cells was measured in a standard 51 Cr-release assay in round-bottom wells as described previously (9). The assay was also performed in flat-bottom wells to determine the effects of CTL migration on killing efficacy in the context of target cells expressing low or high levels of CXCL12 (9).…”