A role for cytomegalovirus-specific CD4+CX3CR1+ T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis.
OBJECTIVE
HIV-infected individuals are at increased risk for myocardial infarction. Given observations that cytomegalovirus (CMV) infection, CMV-specific T cells, and CX3CR1 have each been associated with atherosclerosis, we hypothesized that CMV-induced T-cell immunopathology could contribute to HIV-associated atherosclerosis.


METHODS
We measured the expression of CX3CR1 on peripheral blood mononuclear cells and its association with carotid artery intima-media thickness (IMT) in 29 HIV-infected individuals and 48 uninfected controls. We analyzed the phenotype and specificity of CX3CR1(+)CD4(+) T cells, the production of CX3CL1 (the ligand of CX3CR1) by CMV-infected endothelial cells in vitro, and the migration of CD4(+) T cells induced by CX3CL1.


RESULTS
The progression of atherosclerosis in HIV-infected individuals, as assessed by longitudinal measurements of carotid IMT, was associated with a high frequency of CD4(+) T cells that express the chemokine receptor CX3CR1. Such CD4(+)CX3CR1(+) T cells were antigen-primed, produced high levels of pro-inflammatory cytokines, and composed the majority of the CMV-specific CD4(+) T cells. CMV-stimulated CD4(+) T cells were also found to induce the production of CX3CL1 (the ligand for CX3CR1) by human arterial endothelial cells, driving the transendothelial migration of pro-inflammatory CD4(+) T cells. Finally, we observed that CD4(+)CX3CR1(+) T cells could be localized to the coronary arterial wall in HIV disease.


CONCLUSIONS
HIV-associated atherosclerosis may be driven by a positive feedback pathway in which a high frequency of antigen-stimulated, CMV-specific CD4(+)CX3CR1(+) T cells induce endothelial cells to secrete CX3CL1, which itself drives progressive infiltration of the arterial wall by pro-inflammatory cells.
Division of Experimental Medicine, San Francisco General Hospital, University of California San Francisco, 94110, USA.
Karim
K
Sacre
Peter W
PW
Hunt
Priscilla Y
PY
Hsue
Ekaterina
E
Maidji
Jeffrey N
JN
Martin
Steven G
SG
Deeks
Brigitte
B
Autran
Joseph M
JM
McCune
D000328:Adult; D050197:Atherosclerosis / Q000150:complications / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D054428:Chemokine CX3CL1 / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology*; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine