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A Novel Role for Tumor Necrosis Factor-α in Regulating Susceptibility of Activated CD4+ T Cells From Human and Nonhuman Primates for Distinct Coreceptor Using Lentiviruses

Brice G. T.; Mayne, A. E.; Villinger, F.; Ansari, A. A.
JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2000
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Summary:Although CD4+ T-cell activation has long been shown to promote infection and replication of simian immunodeficiency virus (SIV) and HIV, recent studies have documented that not all activated CD4+ T cells from human and nonhuman primates are susceptible to infection with HIV/SIV, respectively. Activation of CD4+ T cells with anti-CD3 + anti-CD28 conjugated beads led to induction of a state of anti-viral resistance to infection with strains of viruses that primarily use CCR5 as a coreceptor. The studies reported herein were designed to address the mechanism by which anti-CD3 + anti-CD28-Induced stimulation in turn induced antiviral resistance. Results of these studies show that the anti-viral resistance induced by activation of CD4+ T cells with anti-CD3 + anti-CD28 is primarily conferred by the synthesis of tumor necrosis factor-α (TNF-α), and highlight a unique regulatory role for TNF-α in regulating synthesis of MIP-1α, MIP-1β, and regulated-on-activation normal Texpressed and secreted cells, which contributes to this state of antiviral resistance to R5-tropic strains of HIV/SIV. However, while TNF-α has a protective role in antiviral resistance of activated CD4+ T cells to R5-tropic viruses, it enhances CXCR4 expression of CD4+ T cells and mediates increased susceptibility to infection with X4-tropic strains of HIV and recombinant SIVs. The results of the studies reported herein also suggest that it is not the Thl v/s Th2 cytokine profile but the mode of CD4+ T-cell activation that dictates the synthesis of distinct cytokines which regulate the expression of chemokines and chemokine receptors which in turn regulate and confer susceptibility/resistance to R5 v/s X4-tropic HIV and SIV.

Address correspondence and reprint requests to G. T. Brice, Department of Pathology and Laboratory Medicine, Room 4107 B, Winship Cancer Center, 1365B Clifton Road, Emory University School of Medicine, Atlanta, GA 30322, U.S.A.

Manuscript received December 7, 1999; accepted March 7, 2000.

© 2000 Lippincott Williams & Wilkins, Inc.