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. 2011 Sep 24:9:160.
doi: 10.1186/1479-5876-9-160.

The HIV-1 gp120/V3 modifies the response of uninfected CD4 T cells to antigen presentation: mapping of the specific transcriptional signature

Antigone K Morou  1 , Filippos Porichis, Elias Krambovitis, George Sourvinos, Demetrios A Spandidos, Alexandros Zafiropoulos
Affiliations

The HIV-1 gp120/V3 modifies the response of uninfected CD4 T cells to antigen presentation: mapping of the specific transcriptional signature

Antigone K Morou et al. J Transl Med. .

Abstract

Background: 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 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.

Methods: We 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.

Results: Our 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.

Conclusions: Taken 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.

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Figures

Figure 1
Figure 1
Top molecular and cellular functions identified by IPA. (A) IPA categorized genes exhibited significantly altered expression according to their molecular and cellular function. Green and red letters indicate decreased and increased expression, respectively. The number in the parenthesis indicates the number of altered genes classified to a certain function. (B) The diagram shows significantly overrepresented biofunctions. Corrected p-values, based on the Benjamini-Hochberg method of accounting for multiple testing, was applied by IPA to control the error rate in analysis results. A corrected p-value (FDR) of < 0.05 was considered significant.
Figure 2
Figure 2
HIV-1 infection related genes modulated by V3 epitope during the process of antigen presentation. This diagram shows genes associated with HIV-1 infection according to IPA Knowledge Base and their cellular location. Gene products are graphically displayed as nodes. Nodes are further displayed using various shapes that represent the functional class of the gene product. The intensity of the node color indicates the degree of up- (red) or down- (green) regulation.
Figure 3
Figure 3
Top ranked networks identified by IPA. IPA networks that depict associations between genes involved in certain biological functions: (a) Gene Expression, Cellular Development, Hematological System Development and Function (score 38), (b) Cell Cycle, Cancer, Genetic Disorder (score 36), (c) Cellular Growth and Proliferation, Lipid Metabolism, Nucleic Acid Metabolism (score 35), (d) Genetic Disorder, Metabolic Disease, Antimicrobial Response (score 32). The network is graphically displayed with genes/gene products as nodes (different shapes that represent the functional class of the gene product, Figure 2) and the biological relationships between the nodes as edges (lines). The diagrams show direct (solid lines) and indirect (dashed lines) interactions between genes known to orchestrate common functions. The length of an edge reflects the evidence in the literature supporting that node-to-node relationship. Red and green shading denotes genes increased and decreased in expression, respectively, and the intensity of the colour indicates the degree of modulation. Molecules overlaid with orange and purple line are associated with immune response and HIV-1 infection, respectively. The score is derived from a p value and indicates the likelihood of the focus genes in a network to be found together due to random chance.
Figure 4
Figure 4
Significantly enriched canonical pathways identified by IPA. (A) The diagram shows significantly overrepresented canonical pathways. A multiple-testing corrected p-value was calculated using the Benjamini-Hochberg method to control the rate of false discoveries in statistical hypothesis testing. The ratio value represents the number of molecules in a given pathway that meet cut criteria, divided by the total number of molecules that belong to the function. (B) Illustration of altered genes involved in IPA canonical pathway "CD28 signaling in T helper cells". Ingenuity Pathways Analysis software was used to identify altered genes related to canonical apoptotic pathways; red and green colour indicates genes significantly increased and decreased in expression, respectively. Black indicates no significant change in gene expression.
Figure 5
Figure 5
Immunofluorescent staining of the MKi67 antigen. Cells were exposed to V3-coated or control liposomes before activation with SEA for 24 hr (green: Alexa-488 anti-MKi67 rabbit conjugate, blue: To-Pro 3 iodide nuclear staining).
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