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Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection.

ABSTRACT: Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor programmed death (PD)-1 on HIV-1-specific CD4(+) and CD8(+) T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. In this study, we show that PD-1 is upregulated on all T cell subsets, including naive, central memory, and transitional memory T cells in HIV-1-infected subjects. PD-1 is expressed at similar levels on most CD4(+) T cells during the acute and the chronic phase of disease and identifies cells that have recently entered the cell cycle. In contrast, PD-1 expression is dramatically increased in CD8(+) T cells during the transition from acute to chronic infection, and this is associated with reduced levels of cell proliferation. The failure to downregulate expression of PD-1 in most T cells during chronic HIV-1 infection is associated with persistent alterations in the distribution of T cell subsets and is associated with impaired responses to IL-7. Our findings identify PD-1 as a marker for aberrant distribution of T cell subsets in HIV-1 infection.

SUBMITTER: Breton G

PROVIDER: S-EPMC3815464 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection.

Breton Gaëlle G Chomont Nicolas N Takata Hiroshi H Fromentin Rémi R Ahlers Jeffrey J Filali-Mouhim Abdelali A Riou Catherine C Boulassel Mohamed-Rachid MR Routy Jean-Pierre JP Yassine-Diab Bader B Sékaly Rafick-Pierre RP

Journal of immunology (Baltimore, Md. : 1950) 20130805 5

Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor programmed death (PD)-1 on HIV-1-specific CD4(+) and CD8(+) T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. In this study, we show that PD-1 is upregulated on all T c ...[more]

PMID: 23918986

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Project description:Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. However, despite extensive evidence of B-cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, HIV envelope gp140 and CD4 or co-receptor (CoR) binding site (bs) mutant probes were used to evaluate HIV-specific responses in the peripheral blood B cells of individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs (a poorly-neutralizing epitope) arose early whereas those against the CD4bs (a well-characterized neutralizing epitope) were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. These findings were corroborated by transcriptional profiles. Taken together, our findings provide valuable insight into virus-specific B-cell responses in HIV infection and demonstrate that memory B-cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals. HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated (AM) and exhausted (tissue-like; TLM) memory subsets, which are largely absent in the blood of uninfected individuals. These responses are highest during the early stage of HIV infection, significantly decreased following the initiation of antiretroviral therapy (ART), and most importantly, enriched in normal resting memory B cells (RM) when HIV viremia and immune activation are controlled either naturally or as a result of ART. These HIV-specific B cells (AM and TLM) and resting memory B cells (RM) were sorted from peripheral blood mononuclear cells (PBMCs) of 6 HIV infected individuals. In addition, gp140-specific IgG+ B cells were sorted from individuals with either a strong (n= 6) or weak (n= 6) pro-resting memory profile. TaqMan gene expression assay was performed on these HIV-specific B cells and B cell subset. The array consisted of 29 genes.

Project description: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.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.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-1?, IFN-?, TNF, and RANTES (CCR5) activity upstream of the central memory CD4 T cells signature, consistent with the demonstrated milieu in HIV infection.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.

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Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection.

Publications

Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection.

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