SDF-1alpha is a potent inducer of HIV-1-Specific CD8+ T-cell chemotaxis, but migration of CD8+ T cells is impaired at high viral loads

Abstract

Multiple impairments in HIV-1-specific cytotoxic T cells (CTL) have been reported, but derangements in HIV-1-specific CD8+ T-cell chemotaxis have not been described previously. We assessed migration to SDF-1alpha (stromal cell-derived factor 1-alpha) and CX3CL1 in vitro and expression of cognate receptors, CXCR4 and CX3CR1, by flow cytometry in peripheral blood and lymph node CD8+ T cells from HIV-1-seropositive and -seronegative individuals. Compared with seronegative individuals, percentages of CXCR4+CD8+ T cells were reduced (median, 26% versus 74%, p < 0.001) and percentages of CX3CR1+CD8+ T cells were increased (median, 33% versus 15%, p = 0.03) in seropositive individuals. Robust migration of peripheral blood mononuclear cell (PBMC) CD8+ T cells to SDF-1alpha (1 alphag/ml) was observed in both HIV-1-seropositive (median chemotactic index [CI] 4.9) and -seronegative (median CI 2.8) subjects (p = 0.46). CI to SDF-1alpha was not significantly related to percentage of CXCR4+CD8+ T cells or density of CXCR4, but correlated inversely with plasma HIV-1 RNA concentration (r = -0.82, p = 0.03). Little chemotaxis was observed in response to CX3CL1 and it was unrelated to CX3CR1 expression. Lymph node CD8+ T-cell chemotaxis to SDF-1alpha and CX3CL1 in four subjects demonstrated the same patterns observed in PBMC. HIV-1-specific tetramer-staining CD8+ T cells exhibited chemotaxis of similar magnitude as PBMC CD8+ T cells in a subset of subjects. These data suggest that SDF-1alpha is a potent chemoattractant for HIV-1-specific CTL, but that impairments in migration of HIV-1-specific CTL may exist at high viral loads. Improved understanding of the determinants of CTL localization may provide insight into novel therapies to enhance delivery of CTL to sites of HIV-1 replication.

FIG. 1.

Percent and density of cell surface CXCR4 and CX3CR1 on CD8⁺ T cells from HIV-1-seronegative (closed squares) and -seropositive (open circles) individuals. In HIV-1-seropositive subjects, the percent of CXCR4⁺ CD8⁺ T cells was significantly lower (A) and the percent of CX3CR1⁺ CD8⁺ T cells was significantly higher (B) than in HIV-1-seronegative individuals. CXCR4 (C) and CX3CR1 (D) density was similar in HIV-1-seropositive and -seronegative subjects. Horizontal lines indicate medians.

FIG. 2.

Chemotaxis of PBMC CD8⁺ T cells to varying concentrations of SDF-1α and CX3CL1. Dose-dependent CD8⁺ T-cell migration to SDF-1α was demonstrated in both HIV-1-seropositive (A) and seronegative (B) individuals. No consistent relationship between CD8⁺ T-cell chemotaxis and concentration of CX3CL1 was demonstrated in either serogroup (C, D).

FIG. 3.

Chemotaxis of PBMC CD8⁺ T cells to SDF-1α (10⁶ pg/ml) correlated inversely with HIV-1 RNA concentration (r = − 0.82; p = 0.03). Subjects 32, 64, 67, 70, 73, 78, and M14 are included in this graph. *All data points have two replicates; some data point error bars are not visible as replicates are so close in value.

FIG. 4.

Lymph node CD8⁺ T-cell chemotaxis to varying concentrations of SDF-1α (black lines) and CX3CL1 (gray lines) in four HIV-1-seropositive individuals. Lymph node CD8⁺ T-cell migration to SDF-1α was dose dependent and maximal at 10⁶ pg/ml, although migration to CX3CL1 was relatively lower and not consistently related to any specific concentration of CX3CL1.

FIG. 5.

Chemotaxis to SDF-1α (10⁵ pg/ml) was similar for CD8⁺ T cells and HIV-1 tetramer-staining CD8⁺ T cells from PBMC in four HIV-1-seropositive subjects (p = 0.1). Each line represents a paired experiment from one subject with adjacent numbers indicating subject ID number.