Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection
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.
Full-textDOI: · Available from: Mohamed El-Far, Montreal, Oct 01, 2014
- SourceAvailable from: Brian James Willett
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- "It has been known for some time that the quiescence state is actively maintained by factors such as LKLF, Tob, Foxo3a and Foxj1 (Coffer & Burgering, 2004; Tzachanis et al., 2004; Yusuf & Fruman, 2003). The role of these factors in HIV-latency has been explored by few laboratories so far (Haaland et al., 2005; van Grevenynghe et al., 2008) and further research may provide new insights into the mechanism of latency as well as potential therapeutic targets. "
ABSTRACT: Almost 30 years after its initial discovery, infection with the human immunodeficiency virus-1 (HIV-1) remains incurable and the virus persists due to reservoirs of latently infected CD4+ memory T-cells and sanctuary sites within the infected individual where drug penetration is poor. Reactivating latent viruses has been a key strategy to completely eliminate the virus from the host but many difficulties and unanswered questions remain. In this review, the latest developments in HIV-persistence and latency research are presented.Journal of General Virology 01/2013; 94(Pt 5). DOI:10.1099/vir.0.049296-0 · 3.53 Impact Factor
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- "Hence, this provides a molecular mechanism for how homeostatic signals regulate memory T cell persistence (Riou et al., 2007). Moreover, inhibition of Foxo3a expression has been shown to prolong human immunodeficiency virus-specific memory T cell survival, indicating that Foxo3a is a potential target for therapeutic intervention that could promote memory T cell establishment (Riou et al., 2007; van Grevenynghe et al., 2008). "
ABSTRACT: A cardinal feature of adaptive, cytotoxic T lymphocyte (CTL)-mediated immunity is the ability of naïve CTLs to undergo a program of differentiation and proliferation upon activation resulting in the acquisition of lineage-specific T cell functions and eventual establishment of immunological memory. In this review, we examine the molecular factors that shape both the acquisition and maintenance of lineage-specific effector function in virus-specific CTL during both the effector and memory phases of immunity.Frontiers in Immunology 12/2012; 3:371. DOI:10.3389/fimmu.2012.00371
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ABSTRACT: The merging of a new living system, healthy like a neurone or pathologic like a cancer clone, is always a transgression of older ones. It is achieved with the juxtapositions and encasements of previous systems. The new Wholeness is both more and less than the sum of its parts. It merges from the simultaneous metamorphoses of the partners that maintain their identity and their half-autonomy by the preservation of their individual and collective boundaries and their self-organization (like the cell, which merged from Monera. The shuttle of a step of organization “i” to a higher adjacent one “i+1” is the result of the merging of a new spatial and temporal network, through the birth of an Association for the Reciprocal and Mutual Sharing of Advantages and of Disadvantages (ARMSADA). But, all the partners must loss simultaneously the capacity to destroy the other ones. Each advantage for a partner is always a disadvantage for all the others and reciprocally. No one partner is a winner, all are “winner and loser”: ARMSADA is an association "for the best and for the worst". The gain is only for the Wholeness! There is only one rule to survive: "to transform disadvantages into advantages" and "to prevent advantages from turning to disadvantages". When the ecoexotope is changing, a disadvantage can turn to an advantage and conversely. To survive it is "to eat and not to be eaten". Preys or hosts and predators or parasites (like immune cells and HIV) struggle each other in a war without mercy. Each defensive innovation of a prey is followed by an aggressive one of its predators. “To attack” is never the best defence, but “to change” of trophic network. Only the metamorphosis of the endophysiotope makes possible to self-control the dangers. In order that one survives, it is necessary that the others survive first, and reciprocally. The fate of a cancer or HIV-infected cell, like that of a bacterium infected with a phage, is depending on the interactive percolation with its invading virus. That indeed explains the heterogeneity of a disease (cancer or AIDS), its evolutions and the diversity of the potential hosts: "the way is, both, the cause and the consequence of the history." As the previously proposed curative AIDS vaccine, to built with HIV engineered stem cells, the application of this systemic paradigm allows the design of new vaccines, like a curative cancer vaccine and a preventive leprous one. Complementary data, figures and references available at http://www.afscet.asso.fr/resSystemica/Paris05/bricage3.pdf for cell merging, at http://www.minilien.com/?oUtHBBpz46 & at http://hal.archives-ouvertes.fr/hal-00351226/fr for cancer merging and curation, at http://minilien.com/?USaw1HHJ4Z for AIDS curation, and at http://minilien.com/?iUZluv4lpL for leprosy.