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

Abstract

BackgroundHuman 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.MethodsUsing 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.ResultsCentral 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.ConclusionsOur 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 materialThe online version of this article (doi:10.1186/s12864-016-3308-8) contains supplementary material, which is available to authorized users.

Dysregulation of Neuronal Cholesterol Homeostasis upon Exposure to HIV-1 Tat and Cocaine Revealed by RNA-Sequencing

“…Previous studies have investigated changes in the global transcriptome of HIV-1 infected T-cells, B-cells, macrophages and the whole brain. In these studies, functional annotation of DEGs revealed HIV-1 adversely affects the TCA cycle, TGF-β signaling, reductive carboxylate cycle, cytokine-cytokine receptor interaction, cell cycle, DNA repair, apoptosis, immune response pathways and JAK-STAT signaling in PBMCs, CD4+ T cells and monocytes 22 , 47 . RNA-sequencing of HIV-1 infected monocytes and gene ontology analyses uncovered some of the HIV-1 infection specific effects on gene expression and chromatin remodeling 23 .…”

“…HIV-1-mediated changes in the transcriptome of HIV infected cells and tissues revealed widespread alterations in cellular pathways crucial for survival and functioning as well as processes that promote HIV-1 replication. Deep RNA sequencing of CD4+, CD8+ and CD14+ T-cells from PLWH demonstrated HIV-1-mediated changes in the transcriptome of these cells affecting metabolic, cell cycle and lipid profile pathways 21 , 22 . In addition, in HIV-1 infected macrophages, DNA and chromatin alterations have been reported 23 .…”

Human Gene Functional Network-Informed Prediction of HIV-1 Host Dependency Factors

“…To this end, we downloaded a set of T cell microarray data (accession no. GSE73968 ) ( 45 ) from the GEO database ( https://www.ncbi.nlm.nih.gov/geo/ ). The expression level for each gene was further averaged by three replicates.…”

HIV Disease Progression: Overexpression of the Ectoenzyme CD38 as a Contributory Factor?

“…CD38 overexpression in HIV infection could translate in reduced NAD concentration in plasma and/or in T cell cytoplasm, increasing NAD flow from cytoplasm, and surpassing the cell’s capacity to maintain its NAD levels. In consonance with a possible NAD scavenging pressure on intracellular NAD pools, we have found overexpression of nicotinamide phosphoribosyl transferase mRNA (NAMPT), the rate limiting enzyme of the salvage pathway of NAD synthesis) in central memory CD4 T cells from persons living with HIV, [84] which might be compensating NAD removal due to CD38 overexpression. In this way, increased presence of CD38 with an extracellular active site might decrease cytoplasmic NAD concentration.…”