Death of CD4<sup>+</sup>T-Cell Lines Caused by Human Immunodeficiency Virus Type 1 Does Not Depend on Caspases or Apoptosis

Bolton, Diane L.; Hahn, Beom-Ik; Park, Eugenia A.; Lehnhoff, Laura L.; Hornung, Felicita; Lenardo, Michael J.

doi:10.1128/jvi.76.10.5094-5107.2002

Cited by 66 publications

(63 citation statements)

References 65 publications

(63 reference statements)

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“…However, our study evaluating the rate of apoptosis of HIV productively infected cells indicated that apoptosis was marginally enhanced in productively infected cells in comparison with uninfected or bystander cells. This finding is consistent with recent reports 26,35 indicating lack of apoptosis in infected cells on the basis of HIV reporter constructs to discriminate between infected and bystander cells, using multiple apoptosis For personal use only. on May 12, 2018.…”

Section: Discussionsupporting

confidence: 82%

“…Few studies have discriminated between infected and bystander cells, but those studies have relied on infection with a molecular clone of HIV, often depleted in nef and replaced with a reporter such as the green fluorescent protein, 25 mouse heat-stable antigen, 26,27 or surface protein placental alkaline phosphatase. 28 Because these molecular clones are depleted in nef, a physiologic response due to the whole intact virus may not be delineated.…”

Section: Discussionmentioning

confidence: 99%

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Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Bahbouhi

Landay

Al‐Harthi

2004

Blood

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Using intracellular p24 staining to discriminate between bystander and HIV productively infected cells, we evaluated the properties of HIV productively infected cells in terms of cytokine expression, activation status, apoptosis, and cell proliferation. We demonstrate that HIV productively infected primary CD4 ؉ T cells express 12-to 47-fold higher type 1 cytokines than bystander or mock-infected cells. The frequency of HIV productive replication occurred predominantly in Thelper 1 (Th1), followed by Th0, then by Th2 cells. These productively infected cells expressed elevated levels of CD95, CD25, CXC chemokine receptor 4 (CXCR4), and CC chemokine receptor 5 (CCR5). While productively infected cells were only 1.8-fold higher in apoptosis frequency, they up-regulated the antiapoptotic protein B-cell leukemia 2 (Bcl-2) by 10-fold. Up-regulation of interleukin-2 (IL-2) and Bcl-2 were dependent on phosphatidylinositol-3-kinase signal transduction, given that it was down-regulated by Wortmanin treatment. Additionally, 60% of productively infected cells entered the cell cycle, as evaluated by Ki67 staining, but none divided, as evaluated by carboxyfluoresccin diacetate succinimidyl ester (CFSE) staining. Evaluation of cell cycle progression by costaining for DNA and RNA indicated that the cells were arrested in G 2 /M. Collectively, these data indicate that HIV replication occurs predominantly in Th1 cells and is associated with immune activation and up-regulation of Bcl-2, conferring a considerable degree of protection against apoptosis in the productively infected subpopulation. IntroductionThe interaction between cytokines and HIV expression is multifaceted. Approaches to evaluate the relationship between cytokines and HIV have relied on (1) evaluating the impact of a particular cytokine on HIV replication in vitro, [1][2][3][4][5] (2) comparing the cytokine expression profile of HIV-infected and uninfected donors, 6,7 and (3) measuring cytokine production from in vitro infected cells. [8][9][10] Analysis of the impact of cytokines on HIV-1 replication in vitro have generally demonstrated that a number of type 1 cytokines (interleukin-1 [IL-1], tumor necrosis factor-␣ [TNF-␣], IL-2, IL-12) up-regulate HIV replication while type 2 cytokines down-modulate HIV (IL-10, transforming growth factor-␤ [TGF-␤]). This relationship is not simplistic given that a combination of type 1 and type 2 cytokines may lead to a synergistic or antagonistic effects on HIV replication [11][12][13][14] ; this result often depends on the combination of cytokines and on the cell type examined, whether lymphocytic or monocytic.Earlier studies describing the cytokine profile in purified peripheral blood mononuclear cells (PBMCs) from HIV ϩ patients have led to discordant findings. Some suggested that HIV-1 infection leads to a shift from type 1 (IL-2, interferon-␥ [IFN-␥]) to type 2 (IL-4, IL-10) cytokines with HIV disease progression. 6 By contrast, others have not been able to document such a type 1-to-type 2 cytokine shift with disease pro...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Bahbouhi

Landay

Al‐Harthi

2004

Blood

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“…Although a cytotoxic-T-lymphocyte response could contribute to some elimination of infected cells, a strong cellular-mediated immune response to HIV-1/SIV is detectable only late in the depletion time period (43,70). However, we and others have shown that in vitro infection of CD4 ϩ T lymphocytes with HIV-1 leads to direct viral cytopathicity by necrosis (7,11,46). Understanding the mechanism of HIV-1-induced cell death could elucidate the mechanism of T-cell depletion, especially during the early destruction of the mucosal immune system.…”

Section: Aids Results From the Dramatic Loss Of Cd4mentioning

confidence: 99%

Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection

Barnitz

Wan

Tripuraneni

et al. 2010

J Virol

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Infection with human immunodeficiency virus type 1 (HIV-1) causes an inexorable depletion of CD4؉ T cells. The loss of these cells is particularly pronounced in the mucosal immune system during acute infection, and the data suggest that direct viral cytopathicity is a major factor. Cell cycle arrest caused by the HIV-1 accessory protein Vpr is strongly correlated with virus-induced cell death, and phosphorylation of Vpr serine 79 (S79) is required to activate G 2 /M cell cycle blockade. However, the kinase responsible for phosphorylating Vpr remains unknown. Our bioinformatic analyses revealed that S79 is part of a putative phosphorylation site recognized by protein kinase A (PKA). We show here that PKA interacts with Vpr and directly phosphorylates S79. Inhibition of PKA activity during HIV-1 infection abrogates Vpr cell cycle arrest. These findings provide new insight into the signaling event that activates Vpr cell cycle arrest, ultimately leading to the death of infected T cells.

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“…RAW 264.7, Jurkat E6.1, and Jurkat I9.2 (caspase 8-deficient) cells were cultured in complete RPMI 1640 medium. Jurkat cells that stably express Bcl-x L (22) were provided by D. Bolton (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD) and maintained with 400 g/ml G418 in complete RPMI 1640 medium. Human monocyte-derived macrophages (MDM) were generated from elutriated monocytes obtained from healthy adult donors at the National Institutes of Health Clinical Center blood bank.…”

Section: Cells and Transfectionsmentioning

confidence: 99%

The Yersinia Effector Protein YpkA Induces Apoptosis Independently of Actin Depolymerization

Park

Teja

O’Shea

et al. 2007

The Journal of Immunology

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The pathogenicity of the plague agent Yersinia pestis is largely due to the injection of effector proteins that potently block immune responses into host cells through a type III secretion apparatus. One Yersinia effector protein, YpkA, a putative serine/threonine kinase, has been reported to act by depolymerizing actin and disrupting actin microfilament organization. Using YpkA-GFP fusion proteins to directly visualize cells expressing YpkA, we found instead that YpkA triggered rapid cell death that can be blocked by caspase inhibitors and Bcl-xL, but was not dependent on caspase-8. The actin depolymerization promoted by YpkA was only seen in cells with other features of apoptosis, and was blocked by inhibiting apoptosis, indicating that actin filament disruption is likely to be a result, rather than a cause of YpkA-induced apoptosis. A region including aa 133–262 in YpkA was sufficient for inducing apoptosis independent of localization to the plasma membrane. These data suggest that YpkA can act as a direct inducer of cell death.

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Death of CD4⁺T-Cell Lines Caused by Human Immunodeficiency Virus Type 1 Does Not Depend on Caspases or Apoptosis

Cited by 66 publications

References 65 publications

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection

The Yersinia Effector Protein YpkA Induces Apoptosis Independently of Actin Depolymerization

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Death of CD4+T-Cell Lines Caused by Human Immunodeficiency Virus Type 1 Does Not Depend on Caspases or Apoptosis

Cited by 66 publications

References 65 publications

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Protein Kinase A Phosphorylation Activates Vpr-Induced Cell Cycle Arrest during Human Immunodeficiency Virus Type 1 Infection

The Yersinia Effector Protein YpkA Induces Apoptosis Independently of Actin Depolymerization

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Death of CD4⁺T-Cell Lines Caused by Human Immunodeficiency Virus Type 1 Does Not Depend on Caspases or Apoptosis