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BMC Genomics. 2016 Nov 22;17(1):956.

A transcriptome-based model of central memory CD4 T cell death in HIV infection.

Author information

1
Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
2
Computational Genomics Department, Instituto Nacional de Medicina Genómica, Periferico Sur 4809, Mexico City, Mexico.
3
Laboratory of Immunogenomics and Metabolic Diseases, Instituto Nacional de Medicina Genómica, Periferico Sur 4809, Mexico City, Mexico.
4
Department of Virology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico.
5
Infectious Immunopathogenesis Laboratory, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga 15, Mexico City, Mexico.
6
Department of Research in Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Mexico City, Mexico. espinosa@iner.gob.mx.

Abstract

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 Log2 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.

KEYWORDS:

CD4-Positive T-Lymphocytes; Cell Cycle; Cell Death; HIV; Homeostasis; Immunologic Memory; Transcriptome

PMID:
27875993
PMCID:
PMC5120471
DOI:
10.1186/s12864-016-3308-8
[Indexed for MEDLINE]
Free PMC Article

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