Regulation of human immunodeficiency virus type 1 infection, beta-chemokine production, and CCR5 expression in CD40L-stimulated macrophages: immune control of viral entry.
Mononuclear phagocytes (MP) and T lymphocytes play a pivotal role in the host immune response to human immunodeficiency virus type 1 (HIV-1) infection. Regulation of such immune responses can be mediated, in part, through the interaction of the T-lymphocyte-expressed molecule CD40 ligand (CD40L) with its receptor on MP, CD40. Upregulation of CD40L on CD4+ peripheral blood mononuclear cells during advanced HIV-1 disease has previously been reported. Based on this observation, we studied the influence of CD40L-CD40 interactions on MP effector function and viral regulation in vitro. We monitored productive viral infection, cytokine and beta-chemokine production, and beta-chemokine receptor expression in monocyte-derived macrophages (MDM) after treatment with soluble CD40L. Beginning 1 day after infection and continuing at 3-day intervals, treatment with CD40L inhibited productive HIV-1 infection in MDM in a dose-dependent manner. A concomitant and marked upregulation of beta-chemokines (macrophage inhibitory proteins 1alpha and 1beta and RANTES [regulated upon activation normal T-cell expressed and secreted]) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) was observed in HIV-1-infected and CD40L-treated MDM relative to either infected or activated MDM alone. The addition of antibodies to RANTES or TNF-alpha led to a partial reversal of the CD40L-mediated inhibition of HIV-1 infection. Surface expression of CD4 and the beta-chemokine receptor CCR5 was reduced on MDM in response to treatment with CD40L. In addition, treatment of CCR5- and CD4-transfected 293T cells with secretory products from CD40L-stimulated MDM prior to infection with a CCR5-tropic HIV-1 reporter virus led to inhibition of viral entry. In conclusion, we demonstrate that CD40L-mediated inhibition of viral entry coincides with a broad range of MDM immune effector responses and the down-modulation of CCR5 and CD4 expression.
Cotter
R L
RL
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA.
Zheng
J
J
Che
M
M
Niemann
D
D
Liu
Y
Y
He
J
J
Thomas
E
E
Gendelman
H E
HE
D023201:CD40 Ligand / Q000378:metabolism* / Q000494:pharmacology; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000276:immunology; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology; D004279:DNA, Viral / Q000096:biosynthesis; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004279:DNA, Viral; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand