Inhibitory Effects of IFN-γ on HIV-1 Replication in Latently Infected Cells

Sarol, Lilen C.; Imai, Kenichi; Asamitsu, Kaori; Tetsuka, T.; Barzaga, Nina G.; Okamoto, Takashi

doi:10.1006/bbrc.2002.6532

Cited by 21 publications

(13 citation statements)

References 32 publications

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“…After 24 h of incubation, the culture supernatants were collected and assayed for HIV-1 p24 antigen levels. In agreement with previous studies (3,58,64), HIV-1 production was dose-dependently induced by TNF-␣ (Fig. 3A).…”

supporting

confidence: 93%

“…The OM10.1 cells and MOLT4/III B cells were cultured in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, and streptomycin at 37°C in a 5% CO 2 incubator. To maintain the latency in OM10.1 cells, 20 M of AZT was added to culture media and was removed prior to experiments (3,58,59,64).…”

Section: Methodsmentioning

confidence: 99%

“…Experiments were carried out in triplicate and repeated at least twice. The cytotoxicity of the test compound was also determined by the WST-1 method (Roche) (58).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

Victoriano

Asamitsu

Hibi

et al. 2006

Antimicrob Agents Chemother

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supporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

Victoriano

Asamitsu

Hibi

et al. 2006

Antimicrob Agents Chemother

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“…29,30 On the other hand, other reports showed IFN␥ could slow down the Tat-mediated HIV-1 replication rate in the infected cell. 31,32 Here, we showed Tat interferes with the IFN␥-activated Jak/STAT1 signaling pathway. Furthermore, Tat can impair IFN␥-induced STAT1 tyrosine phosphorylation, nuclear translocation, and its consequent GAS-driven gene transcription in PBMos (Figures 1,2).…”

Section: Discussionmentioning

confidence: 85%

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

Cheng¹,

Lin³

et al. 2009

Blood

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IntroductionAIDS is characterized by a profound reduction of CD4 ϩ T lymphocytes, immune defects, and cytokine dysregulation, leading to opportunistic infections and tumorgenesis. 1 HIV-1 has been identified to be the primary etiologic agent. Among HIV-1 gene products, transactivator protein (Tat) is required for efficient viral gene expression by interacting with the HIV long terminal repeat to enhance transcription and RNA processing. 2 Apart from its effects on viral replication, Tat is secreted extracellularly by the infected cells and exerts its paracrine effects on neighboring cells. 3 It has been shown that extracellular Tat may play a diverse role in dysregulating the host immune response via the modulation of cellular gene expression. 4 For example, previous reports including ours showed Tat induces the overexpression of interleukin-10 (IL-10), which is a well known immunosuppressive cytokine capable of down-regulating TH1 cell function and IL-2 synthesis. 5 We recently demonstrated Tat induces IL-10 expression via cellular kinase PKR activity and the activation of transcription factor Ets-1. 6,7 PKR, one of the key genes in the mediation of interferoninduced activities, is a prototype kinase modulated by Tat in HIV-1 perturbation of the cytokine systems. 8 Infection with HIV-1 marks the onset of changes in the microenvironment of the host cell. Throughout all stages of HIV-1 infection, chronic immune activation and dysfunctional cytokine production have been observed. 9 Soluble mediators, including cytokines and viral products such as Tat, produced by the infected cells may enhance the progression of HIV-1 infection either by direct effects or through deregulation of cytokine expression such as interferon-␥ (IFN␥) and tumor necrosis factor-␣ (TNF␣). 7,10 Therefore, elucidating the transcriptional regulation of host genes including cytokines and their regulated pathways upon HIV-1 viral protein stimulation can be used as a tool to delineate the mechanisms of host-virus interactions, and to understand the molecular basis of AIDS pathogenesis.Interferon-␥ is a pleiotropic cytokine produced primarily by T lymphocytes and natural killer (NK) cells in response to viral infection. It is an important mediator with multiple biological activities including macrophage activation, and antimicrobial, antiproliferative, and immunomodulatory effects. 11 It has been shown that IFN␥ receptor-deficient mice are significantly impaired in their abilities to resist infection by microbes including virus, bacteria, and protozoa. 12 Central to IFN␥-induced cellular responses is the activation of Janus kinase-1 (Jak1) and Jak2 and consequent phosphorylation of STAT1. The phosphorylated STAT1 (pSTAT1) undergoes dimerization and translocation into the nucleus, where it binds to IFN␥-activated sequence (GAS) elements present in the promoter of IFN␥-regulated genes, and consequently leads to initiation of transcription. 13 Previous studies of IFN-induced signaling cascade suggested overexpression of suppressor of cytokine signalin...

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“…25 Accordingly, in our model helpless CD8 ϩ T cells also produced decreased amounts of IFN-␥, a cytokine that inhibits viral replication. 42 If these cells behave identically in murine models and humans, they might have diminished cytolytic activity, in addition to their reduced proliferative potential. Future studies are needed to delineate whether the blockage of the TRAIL pathway, e.g., the neutralization of TRAIL by antibody, might be suited to disrupt this deleterious circle and to restore CTL function.…”

Section: Discussionmentioning

confidence: 99%

The TRAIL of Helpless CD8⁺T Cells in HIV Infection

Küerten

Asaad²,

Schoenberger³

et al. 2008

AIDS Research and Human Retroviruses

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Our understanding of how CD4 ϩ T cells can regulate CD8 ϩ T cell responses in HIV infection is still incomplete. Recent evidence obtained in mice suggests that CD4 ϩ T cell help is required for efficient CD8 ϩ T cellmediated immunity in chronic infection: CD8 ϩ T cells primed in the absence of such help release the TNF-related apoptosis-inducing ligand TRAIL and undergo apoptosis. Using a novel ELISPOT assay, in the present study we show that CD8 ϩ T cells are also a source of the antigen-specific TRAIL response in HIV-infected patients with CD4 ϩ T cell counts below 200. In patients with CD4 ϩ T cell counts above 200 TRAIL was not detectable. Accordingly, antigens to which patients have likely been exposed when CD4 ϩ T cell levels were high (e.g., influenza, CMV, and EBV) did not induce TRAIL. Within the HIV-positive donor population with low CD4 ϩ T cell counts a dissociation of the interferon-␥ (IFN-␥) and TRAIL response to different HIV peptide epitopes was detectable suggesting impaired immunity to antigens that triggered TRAIL in the absence of IFN-␥. Our findings emphasize that "helpless" CD8 ϩ T cells, i.e., cells that have been primed in the absence of CD4 ϩ T cell help, may play a crucial role in HIV infection. A "helpless" phenotype may impair CD8 ϩ T cell control of HIV and other infections and possibly contribute to the depletion of CD4 ϩ T cells via apoptosis. Immunizations and infections in this "helpless" state might result in ineffective CD8 ϩ T cell responses. 1175

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Inhibitory Effects of IFN-γ on HIV-1 Replication in Latently Infected Cells

Cited by 21 publications

References 32 publications

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

The TRAIL of Helpless CD8⁺T Cells in HIV Infection

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Inhibitory Effects of IFN-γ on HIV-1 Replication in Latently Infected Cells

Cited by 21 publications

References 32 publications

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling

The TRAIL of Helpless CD8+T Cells in HIV Infection

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The TRAIL of Helpless CD8⁺T Cells in HIV Infection