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 ho st 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 (CD30L) wit h its receptor on MP, CD40. Upregulation of CD40L on CD4(+) peripheral bloo d mononuclear cells during advanced HIV-1 disease has previously been repor ted. Based on this observation, we studied the influence of CD40L-CD40 inte ractions on MP effector function and viral regulation in vitro. We monitore d productive viral infection, cytokine and beta -chemokine production, and beta -chemokine receptor expression in monocyte-derived macrophages (MDM) a fter treatment with soluble CD40L. Beginning 1 day after infection and cont inuing at 3-day intervals, treatment with CD40L inhibited productive HIV-1 infection in MDM in a dose-dependent manner. A concomitant and marked upreg ulation of beta -chemokines (macrophage inhibitory proteins 1 alpha and 1 b eta and RANTES [regulated upon activation normal T-cell expressed and secre ted]) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-alp ha) was observed in HN-l-infected and CD40L-treated MDM relative to either infected or activated MDM alone. The addition of antibodies to RANTES or TN F-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, treat ment of CCR5- and CD4-transfected 293T cells with secretory products from C D40L-stimulated R IDM 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 MD M immune effector responses and the down-modulation of CCR5 and CD4 express ion.