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

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Allocation of HIV-related TCM signature genes in the cell cycle phases they regulate. These genes suggest a promoted progress from G0 to S, followed by arrest in G2/M cell cycle phases, and decreased apoptosis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC5120471&req=5

Fig4: Allocation of HIV-related TCM signature genes in the cell cycle phases they regulate. These genes suggest a promoted progress from G0 to S, followed by arrest in G2/M cell cycle phases, and decreased apoptosis

Mentions: Since the predictions of increased proliferation and increased cytostasis were incompatible, and the prediction of reduced apoptosis did not agree with previous evidence [13, 57–60], we took into account that enrichment tools base their predictions on a broad set of previous findings, ranging from very particular to very general ones. Accordingly, we investigated if the predictions were based on more demarcated processes, and if these processes were compatible. With this purpose, we reviewed the references supporting IPA predictions, allocating the indicated genes to the cell cycle phase that they regulated. We found that genes in all the predictions could be assigned to particular phases in the cell cycle, and implied no conflicts (Fig. 4), with the exception of some proliferation-predicting genes, which did not relate with cell cycle in the supporting evidence.Fig. 4


A transcriptome-based model of central memory CD4 T cell death in HIV infection
Allocation of HIV-related TCM signature genes in the cell cycle phases they regulate. These genes suggest a promoted progress from G0 to S, followed by arrest in G2/M cell cycle phases, and decreased apoptosis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5120471&req=5

Fig4: Allocation of HIV-related TCM signature genes in the cell cycle phases they regulate. These genes suggest a promoted progress from G0 to S, followed by arrest in G2/M cell cycle phases, and decreased apoptosis
Mentions: Since the predictions of increased proliferation and increased cytostasis were incompatible, and the prediction of reduced apoptosis did not agree with previous evidence [13, 57–60], we took into account that enrichment tools base their predictions on a broad set of previous findings, ranging from very particular to very general ones. Accordingly, we investigated if the predictions were based on more demarcated processes, and if these processes were compatible. With this purpose, we reviewed the references supporting IPA predictions, allocating the indicated genes to the cell cycle phase that they regulated. We found that genes in all the predictions could be assigned to particular phases in the cell cycle, and implied no conflicts (Fig. 4), with the exception of some proliferation-predicting genes, which did not relate with cell cycle in the supporting evidence.Fig. 4

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus