Abstract
BackgroundCD4+ T cells are critically important in HIV infection, being both the primary cells infected by HIV and likely playing a direct or indirect role in helping control virus replication. Key areas of interest in HIV vaccine research are mechanisms of viral escape from the immune response. Interestingly, in HIV infection it has been shown that peptide sequence variation can reduce CD4+ T cell responses to the virus, and small changes to peptide sequences can transform agonist peptides into antagonist peptides.ResultsWe describe, at a molecular level, the consequences of antagonism of HIV p24-specific CD4+ T cells. Antagonist peptide exposure in the presence of agonist peptide caused a global suppression of agonist-induced gene expression and signaling molecule phosphorylation. In addition to down-regulation of factors associated with T cell activation, a smaller subset of genes associated with negative regulation of cell activation was up-regulated, including KFL-2, SOCS-1, and SPDEY9P. Finally, antagonist peptide in the absence of agonist peptide also delivered a negative signal to T cells.ConclusionsSmall changes in p24-specific peptides can result in T cell antagonism and reductions of both T cell receptor signaling and activation. These changes are at least in part mediated by a dominant negative signal delivered by antagonist peptide, as evidenced by up-regulation of negative regulatory genes in the presence of agonist plus antagonist stimulation. Antagonism can have dramatic effects on CD4+ T cell function and presents a potential obstacle to HIV vaccine development.
Highlights
CD4+ T cells are critically important in HIV infection, being both the primary cells infected by HIV and likely playing a direct or indirect role in helping control virus replication
Truncated Signal transducer and activator of transcription (STAT) signaling after antagonist exposure To understand the initial activation pathways disrupted in the presence of the antagonist peptide, the phosphorylation state of key molecules in the T cell activation pathway was measured [30,31]
Inflammatory cytokines and chemokines are broadly down-regulated by antagonist exposure Because the STAT-3 and STAT-5 phosphorylation data indicated incomplete activation of the T cells, we sought to determine what other T cell factors were decreased after Ag + Ant stimulation
Summary
CD4+ T cells are critically important in HIV infection, being both the primary cells infected by HIV and likely playing a direct or indirect role in helping control virus replication. There are many studies to date looking at various potential mechanisms of T cell antagonism, including but not limited to systems with T cells expressing dual TCRs where one TCR can antagonize the other (cross-antagonism) [14,15,16,17,18,19,20], with most studies supporting the delivery of a dominant negative signal by antagonist peptides. There is a study showing that T cell antagonism by galectin-1 binding results in truncated TCR signaling and disrupted lipid raft formation at TCR contact sites [24]. Taken together, it is apparent the mechanism of TCR antagonism is likely to vary depending on the model system
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