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

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.