Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection

Laboratoire d'Immunologie, Centre de Recherche, Hôpital Saint-Luc, Centre Hospitalier de l'Université de Montréal, 264 Boulevard Rene-Levesque Est, Montréal, Québec H2X 1P1, Canada.
Nature medicine (Impact Factor: 27.36). 04/2008; 14(3):266-74. DOI: 10.1038/nm1728
Source: PubMed

ABSTRACT The persistence of central memory CD4(+) T cells (T(CM) cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of T(CM) cell decline predicts HIV disease progression. In this study, we show that T(CM) cells and effector memory CD4(+) T cells (T(EM) cells) from HIV(+) elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to T(CM) and T(EM) cells from aviremic successfully treated (ST) subjects or from HIV(-) donors. We show that persistence of T(CM) cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of T(CM) cells from ST subjects to a length of time similar to that of T(CM) cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects.

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Available from: Mohamed El-Far, Montreal, Oct 01, 2014
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    • "Thus, silencing FOXO3a expression inhibits Trp catabolism mediated by CTLA-4-Ig [41]. Furthermore, down-regulation of FOXO3a transcriptional activity in EC represents a molecular signature which can help protect survival of memory T-cells and slow disease progression [42,43]. Our findings suggest a link between distinctive Trp catabolism in EC and a consistently lower FOXO3a expression and IDO activity in these patients. "
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    ABSTRACT: Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naïve, Successfully Treated (ST), and elite controllers (EC). In ART-naïve patients, increased IDO activity/expression, together with elevated levels of TNF-α and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naïve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression.
    PLoS ONE 10/2013; 8(10):e78146. DOI:10.1371/journal.pone.0078146 · 3.23 Impact Factor
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    • "We next performed an exploratory analysis of the mRNA expression of schlafen 11 in central memory and effector memory CD4+ T cell subsets. Multiple reports suggest that elite controllers and long-term non-progressors harbor higher relative numbers of central memory CD4+ T cells, and these cells exhibit distinct phenotypic properties from viremic non-controllers [49,50]. Flow-based sorting was used to isolate central and effector memory populations in a subset of 20 individuals (5 of each disease state), and the CuRe array was implemented to measure restriction gene expression. "
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    ABSTRACT: Several host-encoded antiviral factors suppress HIV-1 replication in a cell-autonomous fashion in vitro. The relevance of these defenses to the control of HIV-1 in vivo remains to be elucidated. We hypothesized that cellular restriction of HIV-1 replication plays a significant role in the observed suppression of HIV-1 in "elite controllers", individuals who maintain undetectable levels of viremia in the absence of antiretroviral therapy (ART). We comprehensively compared the expression levels of 34 host restriction factors and cellular activation levels in CD4+ T cells and sorted T cell subsets between elite controllers, HIV-1-infected (untreated) non-controllers, ART-suppressed, and uninfected individuals. Expression of schlafen 11, a codon usage-based inhibitor of HIV-1 protein synthesis, was significantly elevated in CD4+ T cells from elite controllers as compared to both non-controllers (p=0.048) and ART-suppressed individuals (p=0.024), with this effect most apparent in central memory CD4+ T cells. Schlafen 11 expression levels were comparable between controllers and uninfected individuals. Cumulative restriction factor expression was positively correlated with CD4+ T cell activation (r2=0.597, p<0.0001), viral load (r2=0.34, p=0.015), and expression of ISG15 (r2=0.73, p<0.0001), a marker of interferon exposure. APOBEC3C, APOBEC3D, CTR9, TRIM26, and TRIM32 were elevated in controllers with respect to ART-suppressed individuals, while levels were comparable to uninfected individuals and non-controllers. Host restriction factor expression typically scales with cellular activation levels. However, the elevated mRNA and protein expression of schlafen 11, despite low activation and viral load, violates the global pattern and may be a signature characteristic of HIV-1 elite control.
    Retrovirology 10/2013; 10(1):106. DOI:10.1186/1742-4690-10-106 · 4.19 Impact Factor
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    • "Foxo3a-deficient mice have increased T cell accumulation and magnitude of expanded antigen specific T cells following LCMV infection, but it is debatable whether this is dependent upon T cell intrinsic defects, or extrinsic defects in dendritic cell IL-6 signaling that allows increased T cell viability [34]–[36]. Studies have shown that Foxo3a degradation is important for the survival of human memory CD4+ T cells [37], [38], but the effect of Foxo3a deficiency exclusively in antigen specific CD4+ T cells is largely unresolved and is complicated by the diverse biological pathways in which Foxo3a is an important master regulator. "
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    ABSTRACT: Selective clonal deletion in the CD4(+) T cell compartment during the transition from effector to memory is accompanied by enhanced expression of the pro-apoptotic Bcl-2 family member Bim. Here, we show that Bim deficiency enables the survival of poorly functional Th1 responders that are normally eliminated during contraction. However, rescued bim (-/-) CD4(+) "memory" T cells continued to demonstrate deficient effector functions, poor sensitivity to antigen and an inability to respond to secondary challenge. Our results demonstrate that Bim activity plays a key role in shaping the CD4(+) memory T cell repertoire, ensuring the emergence of highly functional CD4(+) memory T cells and the elimination of Th1 effector cells with sub-optimal function. We propose that Bim is a key mediator of T cell death in the absence of appropriate TCR-driven activation and differentiation.
    PLoS ONE 06/2013; 8(6):e67363. DOI:10.1371/journal.pone.0067363 · 3.23 Impact Factor
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