Acquired T-cell sensitivity to TRAIL mediated killing during HIV infection is regulated by CXCR4-gp120 interactions.
BACKGROUND
Sensitivity towards apoptosis induced by ligation of the tumor necrosis factor family of death receptors is controlled in part by death receptor expression. Whereas cellular activation enhances Fas receptor expression and induces Fas sensitivity, such cellular activation neither alters TRAIL receptor expression nor induces TRAIL sensitivity. Cells infected by HIV acquire sensitivity to TRAIL induced death, although the mechanisms by which this is achieved are undefined.


OBJECTIVE
To define the mechanism by which cells from HIV infected patients acquire sensitivity to TRAIL mediated killing.


METHODS
In vitro assessment of TRAIL receptor expression and TRAIL sensitivity.


METHODS
Treatment of Jurkat T cells, peripheral blood lymphocytes from HIV negative donors, or human osteogenic seroma (HOS) cells expressing CD4, CXCR4 or CCR5 with T tropic gp120, M tropic gp120, or agonistic antibodies against CD4, CXCR4 or CCR5. TRAIL receptors were measured by flow cytometry or reverse transcription-PCR and TRAIL sensitivity was assessed by incubation with recombinant TRAIL followed by Annexin V fluorescein isothiocyanate/Propidium Iodide (PI) staining.


RESULTS
Treatment of uninfected Jurkat T cells, as well as primary T cells with gp120 results in the upregulation of TRAIL death receptor expression and acquired sensitivity to TRAIL mediated cell death. The increase in TRAIL death receptor expression and acquisition of TRAIL sensitivity requires the chemokine coreceptor CXCR4 but not CCR5 or the CD4 receptor.


CONCLUSIONS
These results indicate that chemokine receptor interactions regulate TRAIL receptor expression and provide an explanation for the acquired T cell sensitivity to TRAIL mediated killing death during HIV infection.
Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Julian J
JJ
Lum
David J
DJ
Schnepple
Andrew D
AD
Badley
D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha