Homeostatic chemokines CCL19 and CCL21 promote inflammation in human immunodeficiency virus-infected patients with ongoing viral replication.
CCL19 and CCL21 and their receptor CCR7 are expressed constitutively within lymphoid organs, regulating lymphocyte homing. Recent studies suggest that these chemokines may have inflammatory properties. We hypothesized a role of CCL19/CCL21 in human immunodeficiency virus (HIV) infection by promoting inflammation. We examined the expression of CCL19 and CCL21 in mononuclear cells from peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) in HIV-infected patients before and during highly active anti-retroviral therapy (HAART). We also examined the ability of CCL19/CCL21 to promote inflammatory responses in these patients. PBMC from untreated HIV-infected patients (n = 29) released enhanced levels of CCL19 spontaneously compared with cells from controls (n = 20), particularly in those with symptomatic disease (n = 15, P < 0.01 versus controls). During HAART (n = 9), there was a decrease in the spontaneous CCL19 release and an increase in the phytohaemagglutinin-stimulated CCL19 release in both PBMC (P < 0.01) and BMMC (P < 0.05). In patients with enhanced HIV replication there was an increased proportion of inflammatory CD8(+)CCR7(-)CD45RA(-) T cells in peripheral blood [P < 0.01 and P < 0.05 versus controls, untreated (n = 9) and treatment failure (n = 8), respectively]. In vitro, CCL19/CCL21 promoted an inflammatory response in PBMC when accompanied by high viral load, irrespective of HAART. The HIV-tat protein significantly boosted the inflammatory effect of CCL19/CCL21 in PBMC. These findings link a dysregulated CCL19/CCL21/CCR7 system in HIV-infected patients to persistent inflammation and HIV replication, not only in untreated HIV infection, but also in treatment failure during HAART.
Damås
J K
JK
Research Institute for Internal Medicine, University of Oslo, Oslo, Norway. jan.k.damas@ntnu.no
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Heggelund
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Fløisand
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Halvorsen
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Frøland
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D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001854:Bone Marrow Cells / Q000737:chemistry; D016022:Case-Control Studies; D054415:Chemokine CCL19 / Q000032:analysis / Q000276:immunology*; D054421:Chemokine CCL21 / Q000032:analysis / Q000276:immunology*; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006706:Homeostasis; D006801:Humans; D007156:Immunologic Memory; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008297:Male; D054400:Receptors, CCR7 / Q000032:analysis; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology*; D017211:Treatment Failure; D019562:Viral Load; D014779:Virus Replication; D055815:Young Adult
D019380:Anti-HIV Agents; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054400:Receptors, CCR7