Abstract
BackgroundThe asymptomatic phase of HIV-1 infection is characterized by a progressive depletion of uninfected peripheral effector/memory CD4+ T cells that subsequently leads to immune dysfunction and AIDS symptoms. We have previously demonstrated that the presence of specific gp120/V3 peptides during antigen presentation can modify the activation of normal T-cells leading to altered immune function. The aim of the present study was to map the specific transcriptional profile invoked by an HIV-1/V3 epitope in uninfected T cells during antigen presentation.MethodsWe exposed primary human peripheral blood monocytes to V3 lipopeptides using a liposome delivery system followed by a superantigen-mediated antigen presentation system. We then evaluated the changes in the T-cell transcriptional profile using oligonucleotide microarrays and performed Ingenuity Pathway Analysis (IPA) and DAVID analysis. The results were validated using realtime PCR, FACS, Western blotting and immunofluorescence.ResultsOur results revealed that the most highly modulated transcripts could almost entirely be categorized as related to the cell cycle or transcriptional regulation. The most statistically significant enriched categories and networks identified by IPA were associated with cell cycle, gene expression, immune response, infection mechanisms, cellular growth, proliferation and antigen presentation. Canonical pathways involved in energy and cell cycle regulation, and in the co-activation of T cells were also enriched.ConclusionsTaken together, these results document a distinct transcriptional profile invoked by the HIV-1/V3 epitope. These data could be invaluable to determine the underlying mechanism by which HIV-1 epitopes interfere with uninfected CD4+ T-cell function causing hyper proliferation and AICD.
Highlights
The asymptomatic phase of HIV-1 infection is characterized by a progressive depletion of uninfected peripheral effector/memory CD4+ T cells that subsequently leads to immune dysfunction and AIDS symptoms
The asymptomatic phase of HIV-1 infection is characterized by the progressive depletion of uninfected peripheral effector/memory (CD45RO+) CD4+ T cells [1] that leads to subsequent immunodeficiency and AIDS symptoms
We have shown previously that antigen presentation can be deregulated by the presence of V3 epitopes on the surface of macrophages
Summary
The asymptomatic phase of HIV-1 infection is characterized by a progressive depletion of uninfected peripheral effector/memory CD4+ T cells that subsequently leads to immune dysfunction and AIDS symptoms. We have previously demonstrated that the presence of specific gp120/V3 peptides during antigen presentation can modify the activation of normal T-cells leading to altered immune function. The asymptomatic phase of HIV-1 infection is characterized by the progressive depletion of uninfected peripheral effector/memory (CD45RO+) CD4+ T cells [1] that leads to subsequent immunodeficiency and AIDS symptoms. We have shown previously that antigen presentation can be deregulated by the presence of V3 epitopes on the surface of macrophages. CCR5 is one of the main mediators of V3-induced intracellular signaling during antigen presentation which leads to AICD, the V3CCR5 interaction itself being of ionic nature [14,15]. Microarray studies utilizing the whole gp120 have shown increased expression of genes belonging to mitogen-activated protein kinase signal transduction pathways and genes regulating cell cycle in PBMCs [13,16]
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