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A transcriptome-based model of central memory CD4 T cell death in HIV infection
BACKGROUND: Human central memory CD4 T cells are characterized by their capacity of proliferation and differentiation into effector memory CD4 T cells. Homeostasis of central memory CD4 T cells is considered a key factor sustaining the asymptomatic stage of Human Immunodeficiency Virus type 1 (HIV-1...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120471/ https://www.ncbi.nlm.nih.gov/pubmed/27875993 http://dx.doi.org/10.1186/s12864-016-3308-8 |
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author | Olvera-García, Gustavo Aguilar-García, Tania Gutiérrez-Jasso, Fany Imaz-Rosshandler, Iván Rangel-Escareño, Claudia Orozco, Lorena Aguilar-Delfín, Irma Vázquez-Pérez, Joel A. Zúñiga, Joaquín Pérez-Patrigeon, Santiago Espinosa, Enrique |
author_facet | Olvera-García, Gustavo Aguilar-García, Tania Gutiérrez-Jasso, Fany Imaz-Rosshandler, Iván Rangel-Escareño, Claudia Orozco, Lorena Aguilar-Delfín, Irma Vázquez-Pérez, Joel A. Zúñiga, Joaquín Pérez-Patrigeon, Santiago Espinosa, Enrique |
author_sort | Olvera-García, Gustavo |
collection | PubMed |
description | BACKGROUND: Human central memory CD4 T cells are characterized by their capacity of proliferation and differentiation into effector memory CD4 T cells. Homeostasis of central memory CD4 T cells is considered a key factor sustaining the asymptomatic stage of Human Immunodeficiency Virus type 1 (HIV-1) infection, while progression to acquired immunodeficiency syndrome is imputed to central memory CD4 T cells homeostatic failure. We investigated if central memory CD4 T cells from patients with HIV-1 infection have a gene expression profile impeding proliferation and survival, despite their activated state. METHODS: Using gene expression microarrays, we analyzed mRNA expression patterns in naive, central memory, and effector memory CD4 T cells from healthy controls, and naive and central memory CD4 T cells from patients with HIV-1 infection. Differentially expressed genes, defined by Log(2) Fold Change (FC) ≥ |0.5| and Log (odds) > 0, were used in pathway enrichment analyses. RESULTS: Central memory CD4 T cells from patients and controls showed comparable expression of differentiation-related genes, ruling out an effector-like differentiation of central memory CD4 T cells in HIV infection. However, 210 genes were differentially expressed in central memory CD4 T cells from patients compared with those from controls. Expression of 75 of these genes was validated by semi quantitative RT-PCR, and independently reproduced enrichment results from this gene expression signature. The results of functional enrichment analysis indicated movement to cell cycle phases G1 and S (increased CCNE1, MKI67, IL12RB2, ADAM9, decreased FGF9, etc.), but also arrest in G2/M (increased CHK1, RBBP8, KIF11, etc.). Unexpectedly, the results also suggested decreased apoptosis (increased CSTA, NFKBIA, decreased RNASEL, etc.). Results also suggested increased IL-1β, IFN-γ, TNF, and RANTES (CCR5) activity upstream of the central memory CD4 T cells signature, consistent with the demonstrated milieu in HIV infection. CONCLUSIONS: Our findings support a model where progressive loss of central memory CD4 T cells in chronic HIV-1 infection is driven by increased cell cycle entry followed by mitotic arrest, leading to a non-apoptotic death pathway without actual proliferation, possibly contributing to increased turnover. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-3308-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5120471 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-51204712016-11-28 A transcriptome-based model of central memory CD4 T cell death in HIV infection Olvera-García, Gustavo Aguilar-García, Tania Gutiérrez-Jasso, Fany Imaz-Rosshandler, Iván Rangel-Escareño, Claudia Orozco, Lorena Aguilar-Delfín, Irma Vázquez-Pérez, Joel A. Zúñiga, Joaquín Pérez-Patrigeon, Santiago Espinosa, Enrique BMC Genomics Research Article BACKGROUND: Human central memory CD4 T cells are characterized by their capacity of proliferation and differentiation into effector memory CD4 T cells. Homeostasis of central memory CD4 T cells is considered a key factor sustaining the asymptomatic stage of Human Immunodeficiency Virus type 1 (HIV-1) infection, while progression to acquired immunodeficiency syndrome is imputed to central memory CD4 T cells homeostatic failure. We investigated if central memory CD4 T cells from patients with HIV-1 infection have a gene expression profile impeding proliferation and survival, despite their activated state. METHODS: Using gene expression microarrays, we analyzed mRNA expression patterns in naive, central memory, and effector memory CD4 T cells from healthy controls, and naive and central memory CD4 T cells from patients with HIV-1 infection. Differentially expressed genes, defined by Log(2) Fold Change (FC) ≥ |0.5| and Log (odds) > 0, were used in pathway enrichment analyses. RESULTS: Central memory CD4 T cells from patients and controls showed comparable expression of differentiation-related genes, ruling out an effector-like differentiation of central memory CD4 T cells in HIV infection. However, 210 genes were differentially expressed in central memory CD4 T cells from patients compared with those from controls. Expression of 75 of these genes was validated by semi quantitative RT-PCR, and independently reproduced enrichment results from this gene expression signature. The results of functional enrichment analysis indicated movement to cell cycle phases G1 and S (increased CCNE1, MKI67, IL12RB2, ADAM9, decreased FGF9, etc.), but also arrest in G2/M (increased CHK1, RBBP8, KIF11, etc.). Unexpectedly, the results also suggested decreased apoptosis (increased CSTA, NFKBIA, decreased RNASEL, etc.). Results also suggested increased IL-1β, IFN-γ, TNF, and RANTES (CCR5) activity upstream of the central memory CD4 T cells signature, consistent with the demonstrated milieu in HIV infection. CONCLUSIONS: Our findings support a model where progressive loss of central memory CD4 T cells in chronic HIV-1 infection is driven by increased cell cycle entry followed by mitotic arrest, leading to a non-apoptotic death pathway without actual proliferation, possibly contributing to increased turnover. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-3308-8) contains supplementary material, which is available to authorized users. BioMed Central 2016-11-22 /pmc/articles/PMC5120471/ /pubmed/27875993 http://dx.doi.org/10.1186/s12864-016-3308-8 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Olvera-García, Gustavo Aguilar-García, Tania Gutiérrez-Jasso, Fany Imaz-Rosshandler, Iván Rangel-Escareño, Claudia Orozco, Lorena Aguilar-Delfín, Irma Vázquez-Pérez, Joel A. Zúñiga, Joaquín Pérez-Patrigeon, Santiago Espinosa, Enrique A transcriptome-based model of central memory CD4 T cell death in HIV infection |
title | A transcriptome-based model of central memory CD4 T cell death in HIV infection |
title_full | A transcriptome-based model of central memory CD4 T cell death in HIV infection |
title_fullStr | A transcriptome-based model of central memory CD4 T cell death in HIV infection |
title_full_unstemmed | A transcriptome-based model of central memory CD4 T cell death in HIV infection |
title_short | A transcriptome-based model of central memory CD4 T cell death in HIV infection |
title_sort | transcriptome-based model of central memory cd4 t cell death in hiv infection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120471/ https://www.ncbi.nlm.nih.gov/pubmed/27875993 http://dx.doi.org/10.1186/s12864-016-3308-8 |
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