Could Nef and Vpr Proteins Contribute to Disease Progression by Promoting Depletion of Bystander Cells and Prolonged Survival of HIV-Infected Cells?

Azad, Ahmed A.

doi:10.1006/bbrc.1999.1708

Cited by 54 publications

(31 citation statements)

References 129 publications

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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: 92%

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: 92%

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

Bahbouhi

Landay

Al‐Harthi

2004

Blood

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“…The mechanism of Vpr-induced apoptosis is unclear (22,42,51) and may or may not be related to the mechanism of G 2 arrest by Vpr (10,35). Importantly, the apoptotic activity of Vpr is a recognized pathogenic factor in HIV-1 infection, contributing significantly to HIV-induced apoptosis of infected and bystander cells (2,23,29,42). Given that Hsp70 reduces Vpr-induced G 2 arrest, we investigated the effect of Hsp70 on Vpr-dependent apoptosis associated with HIV-1 infection.…”

Section: Resultsmentioning

confidence: 99%

Heat Shock Protein 70 Protects Cells from Cell Cycle Arrest and Apoptosis Induced by Human Immunodeficiency Virus Type 1 Viral Protein R

Iordanskiy

Zhao

Dubrovsky

et al. 2004

J Virol

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Heat shock proteins (HSPs) are produced in cells in response to a range of stress-related stimuli, including heat, UV radiation, and microbial/viral infections. In addition to previously recognized activity of HSPs as facilitators of protein folding and chaperones, recent studies revealed unique properties of HSPs in generating specific immune responses against cancers and infectious agents (reviewed in reference 3). More-

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“…The N-terminal portion of Nef has been found to be involved in apoptosis of uninfected lymphocytes (5,31). Okada and colleagues have shown that soluble, exogenous Nef protein, in complex with anti-Nef antibodies, causes destruction of a broad spectrum of uninfected lymphoid cells (i.e., CD4 ϩ and CD8 ϩ T lymphocytes, B lymphocytes, macrophages, and neutrophils), leading to suppression of the immune system (46)(47)(48)(49).…”

Section: Finkel Et Al Reported That Apoptosis Was Observed In Cd4mentioning

confidence: 99%

Extracellular Nef Protein Targets CD4⁺T Cells for Apoptosis by Interacting with CXCR4 Surface Receptors

James¹,

Huang²,

Khan³

et al. 2004

J Virol

114

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The effects of soluble Nef protein on CD4؉ T cells were examined. CD4 ؉ -T-cell cultures exposed to soluble Nef were analyzed for apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and hallmarks of apoptosis including cytoplasmic shrinkage, nuclear fragmentation, DNA laddering, and caspase activation. We observed dose-and time-dependent inductions of apoptosis. DNA laddering and activated caspase 3 were also evident. Cells treated with Nef/protein kinase inhibitor complexes were protected from Nef-induced apoptosis, suggesting possible roles for protein kinases in the apoptosis pathway. Similarly, cells treated with Nef/anti-Nef antibody complexes were protected from Nef-induced apoptosis. The cellular receptor responsible for Nef-induced apoptosis was identified through antibody-and ligand-blocking experiments as a receptor commonly involved in viral entry. CXCR4 antibodies, as well as the endogenous ligand SDF-1␣, were effective in blocking Nef-induced apoptosis, while CCR5 and CD4 antibodies were ineffective. Moreover, a CXCR4-deficient cell line, MDA-MB-468, which was resistant to Nef-induced apoptosis, became sensitive upon transfection with a CXCR4-expressing vector. This study suggests that extracellular Nef protein could contribute to the decline of CD4 counts prior to and during the onset of AIDS in patients with human immunodeficiency virus type 1 infections.

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Could Nef and Vpr Proteins Contribute to Disease Progression by Promoting Depletion of Bystander Cells and Prolonged Survival of HIV-Infected Cells?

Cited by 54 publications

References 129 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

Heat Shock Protein 70 Protects Cells from Cell Cycle Arrest and Apoptosis Induced by Human Immunodeficiency Virus Type 1 Viral Protein R

Extracellular Nef Protein Targets CD4⁺T Cells for Apoptosis by Interacting with CXCR4 Surface Receptors

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Could Nef and Vpr Proteins Contribute to Disease Progression by Promoting Depletion of Bystander Cells and Prolonged Survival of HIV-Infected Cells?

Cited by 54 publications

References 129 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

Heat Shock Protein 70 Protects Cells from Cell Cycle Arrest and Apoptosis Induced by Human Immunodeficiency Virus Type 1 Viral Protein R

Extracellular Nef Protein Targets CD4+T Cells for Apoptosis by Interacting with CXCR4 Surface Receptors

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Extracellular Nef Protein Targets CD4⁺T Cells for Apoptosis by Interacting with CXCR4 Surface Receptors