A novel role for tumor necrosis factor-alpha 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 an d replication of simian immunodeficiency virus (SIV) and HIV, recent studie s have documented that not all activated CD4+ T cells from human and nonhum an primates are susceptible to infection with HIV/SIV, respectively. Activa tion of CD4(+) T cells with anti-CD3 + anti-CD28 conjugated beads led to in duction of a state of anti-viral resistance to infection with strains of vi ruses that primarily use CCR5 as a coreceptor. The studies reported herein were designed to address the mechanism by which anti-CDS + anti-CD28-induce d stimulation in turn induced antiviral resistance. Results of these studie s 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-alpha (TNF-alpha), and highlight a unique regulatory role for TNF-alpha in regulating synthesis of MIP-1 alpha, MIP-1 beta, and regul ated-on-activation normal T expressed and secreted cells, which contributes to this state of antiviral resistance to RS-tropic strains of HIV/SIV. How ever, while TNF-alpha has a protective role in antiviral resistance of acti vated CD4+ T cells to R5-tropic viruses, it enhances CXCR4 expression of CD 4+ T cells and mediates increased susceptibility to infection with X4-tropi c strains of HIV and recombinant SIVs. The results of the studies reported herein also suggest that it is not the Th1 v/s Th2 cytokine profile but the mode of CD4(+) T-cell activation that dictates the synthesis of distinct c ytokines which regulate the expression of chemokines and chemokine receptor s which in rum regulate and confer susceptibility/resistance to R5 v/s X4-t ropic HIV and SIV.