In vivoHIV-1 infection of CD45RA+CD4+T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4+T cell decline

Blaak, Hetty; Wout, Angélique B. van‘t; Brouwer, Margreet; Hooibrink, Berend; Hovenkamp, E.; Schuitemaker, Hanneke

doi:10.1073/pnas.97.3.1269

Cited by 233 publications

(188 citation statements)

References 41 publications

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“…Both naïve and memory subsets (CD45RO + and CD45RO − ) of CD4 + T cells were infected in lymphoid organs similar to HIV-infected patients [127]. Importantly, the depletion of naïve T cells is dramatically seen in both HIVinfected patients and highly pathogenic SHIV infection in macaques, and there is direct evidence correlating CXCR4 emergence with a dramatic depletion of naïve T cells and rapid clinical progression [128].…”

Section: Hiv-1 Pathogenesis In the Humanized Mouse Modelmentioning

confidence: 82%

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

et al. 2008

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FoxP3 + CD4 + CD25 + regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly understood due to lack of a robust model. We summarize here the regulation and function of Foxp3 in Treg cells and in modulating HIV-1 replication. Based on recent findings from SIV/monkey and HIV/humanized mouse models, a model of the dual role of Treg cells in HIV-1 infection and immuno-pathogenesis is discussed. KeywordsRegulatory T cells; AIDS; Chromatin; Epigenetic; Humanized mouse; DKO-hu; ONTAK Regulatory T cells play an important role in self immune tolerance and in balanced immune responsesThe regulation of immune tolerance is a critical aspect of immunology. The balance between recognition of self versus non-self is essential for maintenance of immune homeostasis. Regulatory T cells (CD4 + CD25 + ) are a crucial component for the control of deleterious effects from excessive immune responses as seen in autoimmune disease or allergic insult [1,2]. Treg cells have been implicated in a number of pathologic processes including elevated levels in cancers [3][4][5] and infectious diseases [6][7][8][9], and reduced levels in autoimmune diseases [1,[10][11][12][13]. It is apparent that Treg cells are induced (or recruited and expanded) by most infections to modulate host immune responses to avoid overreactive immunity (Fig. 1). As a result, Treg play a critical role in immune responses, vaccinations as well as in immunopathogenesis of pathogens. For example, Leishmania infection leads to induction of Treg that help to maintain the balance of immune response and pathogen persistence [18,19]. For the host, persistence of the pathogen is beneficial to maintain effective immunity against these pathogens [18]. In a number of chronic viral infections, Treg are induced to subdue the anti-viral immune responses and allow persistent infection. Mechanisms of CD4 T-cell differentiationT-cell lineage commitment and activation of T cells are usually accompanied by changes in patterns of gene expression. During T-cell responses, T helper (Th) progenitor cells will undergo Th1 or Th2 lineage commitments involving well-defined initiation cytokines, transcription factors, and effector cytokines. Expression of T-bet and GATA3 in Th1 and Th2 cells, respectively, is epigenetically regulated by histone modification and DNA methylation. As T lineage determinants, T-bet or GATA3 are also involved in epigenetically reprogramming the T-cell genome to silence the Th2 or Th1 effector cytokines, respectively, and to activate Th1 or Th2 cytokine genes for transcription (Fig. 2). Similarly, Th17 cell differentiation requires IL-6/TGF-β (mo...

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Section: Hiv-1 Pathogenesis In the Humanized Mouse Modelmentioning

confidence: 82%

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

et al. 2008

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“…15,[47][48][49][50] A positive correlation between CD4 þ T cell decline and infection by syncytium-inducing HIV-1 or SIV-1 variants has been established in vitro 15,20,48,51 and, more importantly, in vivo, in humans with AIDS, 47,49 humanized SCID mice, 52 and monkeys. 53 We have studied several in vitro models of syncytial apoptosis, in particular a coculture system involving HeLa cells transfected with the HIV-1 LAI Env gene and HeLa cells transfected with CD4.…”

Section: Syncytial Apoptosis Induced By Envmentioning

confidence: 98%

Mechanisms of apoptosis induction by the HIV-1 envelope

et al. 2005

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The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by a cornucopia of distinct mechanisms. A soluble Env derivative, gp120, can kill cells through signals that are transmitted by chemokine receptors such as CXCR4. Cell surface-bound Env (gp120/gp41), as present on the plasma membrane of HIV-1-infected cells, can kill uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by at least three different mechanisms.

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“…[7][8][9][10] This type of bystander killing often involves cell-to-cell fusion events that lead to the formation of syncytia. Such syncytia are relatively rare in lymphoid tissues from HIV-1-infected patients, 11,12 perhaps due to their short half-live. However, syncytia dubbed as "giant multinuclear cells" are pathognonomic for the diagnosis of HIV-1-associated encephalitis (also called "neuro-AIDS"), a neurodegenerative condition that leads to dementia.…”

Section: Introductionmentioning

confidence: 99%

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

Séror¹,

Raza²,

Brottes³

et al. 2009

Cell Cycle

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Fusogenic HIV-1 isolates induce the fusion of infected and bystander cells. Such syncytia can be found as "multinucleated giant cells" in the brain from HIV-1-infected individuals, as well as in lymphoid tissues. Syncytia elicited by the HIV-1 envelope glycoprotein (Env) manifest the aggregation of PML in discrete nuclear bodies and the recruitment of TopBP1, NBS1 and ATM to DNA damage foci containing phosphorylated ATM and histone H2AX (g-H2AX). This DNA damage response then culminates in p53-dependent activation of the mitochondrial pathway of apoptosis. Here, we show that Env-elicited syncytia also manifest activating phosphorylations of the checkpoint kinases 1 and 2 (Chk1 and Chk2), and both Chk1 and Chk2 colocalize with g-H2AX foci. However, only the siRNA-mediated knockdown of Chk2, not the depletion of Chk1, inhibits mitochondrial outer membrane permeabilization and subsequent syncytial apoptosis. Depletion of PML, TopBP1, NBS1 or ATM inhibit the activating phosphorylation of Chk2. Altogether, these results indicate that Chk2 (but not Chk1) participates in the DNA damage-elicited proapoptotic cascade that leads to the demise of Env-elicited syncytia.

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In vivoHIV-1 infection of CD45RA⁺CD4⁺T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4⁺T cell decline

Cited by 233 publications

References 41 publications

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

Mechanisms of apoptosis induction by the HIV-1 envelope

Pro-apoptotic function of checkpoint kinase-2 in syncytia elicited by the HIV-1 envelope

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