scholarly journals Distinct Mechanisms of CD4+ and CD8+ T-Cell Activation and Bystander Apoptosis Induced by Human Immunodeficiency Virus Type 1 Virions

2005 ◽  
Vol 79 (10) ◽  
pp. 6299-6311 ◽  
Author(s):  
Geoffrey H. Holm ◽  
Dana Gabuzda
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Apoptosis of uninfected bystander T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 envelope/receptor interactions and immune activation have been implicated as contributors to bystander apoptosis. To better understand the relationship between T-cell activation and bystander apoptosis during HIV-1 pathogenesis, we investigated the effects of the highly cytopathic CXCR4-tropic HIV-1 variant ELI6 on primary CD4+ and CD8+ T cells. Infection of primary T-cell cultures with ELI6 induced CD4+ T-cell depletion by direct cell lysis and bystander apoptosis. Exposure of primary CD4+ and CD8+ T cells to nonreplicating ELI6 virions induced bystander apoptosis through a Fas-independent mechanism. Bystander apoptosis of CD4+ T cells required direct contact with virions and Env/CXCR4 binding. In contrast, the apoptosis of CD8+ T cells was triggered by a soluble factor(s) secreted by CD4+ T cells. HIV-1 virions activated CD4+ and CD8+ T cells to express CD25 and HLA-DR and preferentially induced apoptosis in CD25+HLA-DR+ T cells in a CXCR4-dependent manner. Maximal levels of binding, activation, and apoptosis were induced by virions that incorporated MHC class II and B7-2 into the viral membrane. These results suggest that nonreplicating HIV-1 virions contribute to chronic immune activation and T-cell depletion during HIV-1 pathogenesis by activating CD4+ and CD8+ T cells, which then proceed to die via apoptosis. This mechanism may represent a viral immune evasion strategy to increase viral replication by activating target cells while killing immune effector cells that are not productively infected.

scholarly journals Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1741-1746 ◽  
Author(s):  
CB Baumler ◽  
T Bohler ◽  
I Herr ◽  
A Benner ◽  
PH Krammer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.

scholarly journals Costimulation of T-cell activation and virus production by B7 antigen on activated CD4+ T cells from human immunodeficiency virus type 1-infected donors

1993 ◽  
Vol 90 (23) ◽  
pp. 11094-11098 ◽  
Author(s):  
O K Haffar ◽  
M D Smithgall ◽  
J Bradshaw ◽  
B Brady ◽  
N K Damle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
T Cell Lines ◽  
Antigen Presenting ◽  
Hiv 1

Infection with the human immunodeficiency virus type 1 (HIV-1) requires T-cell activation. Recent studies have shown that interactions of the T-lymphocyte receptors CD28 and CTLA-4 with their counter receptor, B7, on antigen-presenting cells are required for optimal T-cell activation. Here we show that HIV-1 infection is associated with decreased expression of CD28 and increased expression of B7 on CD4+ T-cell lines generated from seropositive donors by alloantigen stimulation. Loss of CD28 expression was not seen on CD4+ T-cell lines from seronegative donors, but up-regulation of B7 expression was observed upon more prolonged culture. Both T-cell proliferation and interleukin 2 mRNA accumulation in HIV-1-infected cultures required costimulation with exogenous B7 because these events were blocked by CTLA4Ig, a soluble form of CTLA-4 that binds B7 with high avidity. In contrast, levels of HIV-1 RNA were not affected by CTLA4Ig, indicating that regulation of virus transcription in these cultures did not depend upon CD28-B7 engagement. Infected T cells could present alloantigen to fresh, uninfected CD4+ T cells, leading to increased proliferation and virus spread to the activated cells. Both of these events were blocked by CTLA4Ig. Thus, chronic activation of HIV-1-infected CD4+ T cells reduces expression of CD28 and increases expression of B7, thereby enabling these T cells to become antigen-presenting cells for uninfected CD4+ T cells; this might be another mechanism for HIV-1 transmission via T-cell-T-cell contact.

scholarly journals Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1741-1746 ◽  
Author(s):  
CB Baumler ◽  
T Bohler ◽  
I Herr ◽  
A Benner ◽  
PH Krammer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Hiv 1

Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.

scholarly journals Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics

2007 ◽  
Vol 82 (4) ◽  
pp. 1870-1883 ◽  
Author(s):  
Ahmad R. Sedaghat ◽  
Jennifer German ◽  
Tanya M. Teslovich ◽  
Joseph Cofrancesco ◽  
Chunfa C. Jie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The mechanism of CD4+ T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4+ T-cell activation. We assumed that the pathogenic process of excessive CD4+ T-cell activation would be reflected in the transcriptional profiles of activated CD4+ T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4+ T cells from untreated HIV-positive (HIV+) individuals are clearly different from those of activated CD4+ T cells from HIV-negative (HIV−) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4+ T cells of untreated HIV+ individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4+ T cells of untreated HIV+ individuals compared to those of HIV− individuals. We confirm these findings by examination of in vivo-activated CD4+ T cells. Taken together, these results suggest that activated CD4+ T cells from untreated HIV+ individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4+ T-cell depletion during chronic HIV-1 infection.

scholarly journals Adult AIDS-Like Disease in a Novel Inducible Human Immunodeficiency Virus Type 1 Nef Transgenic Mouse Model: CD4+ T-Cell Activation Is Nef Dependent and Can Occur in the Absence of Lymphophenia

2009 ◽  
Vol 83 (22) ◽  
pp. 11830-11846 ◽  
Author(s):  
Mir Munir Ahmed Rahim ◽  
Pavel Chrobak ◽  
Chunyan Hu ◽  
Zaher Hanna ◽  
Paul Jolicoeur
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT CD4C/HIVnef transgenic (Tg) mice express Nef in CD4+ T cells and in the cells of the macrophage/monocyte/dendritic lineage, and they develop an AIDS-like disease similar to human AIDS. In these mice, Nef is constitutively expressed throughout life. To rule out the contribution of any developmental defects caused by early expression of Nef, we generated inducible human immunodeficiency virus type 1 (HIV-1) Nef Tg mice by using the tetracycline-inducible system. Faithful expression of the Nef transgene was induced in (CD4C/rtTA × TRE/HIVNef) or (CD4C/rtTA2S-M2 × TRE/HIVNef) double-Tg mice upon doxycycline (DOX) treatment in drinking water. Long-term treatment of these mice with DOX also led to loss, apoptosis, and activation of CD4+ T cells, this latter phenotype being observed even with low levels of Nef. These phenotypes could be transferred by bone marrow (BM) transplantation, indicating a hematopoietic cell autonomous effect. In addition, in mixed Tg:non-Tg BM chimeras, only Tg and not non-Tg CD4+ T cells exhibited an effector/memory phenotype in the absence of lymphopenia. Finally, the DOX-induced double-Tg mice developed nonlymphoid organ diseases similar to those of CD4C/HIVNef Tg mice and of humans infected with HIV-1. These results show for the first time that adult mice are susceptible to the detrimental action of Nef and that Nef-mediated T-cell activation can be independent of lymphopenia. These Tg mice represent a unique model which is likely to be instrumental for understanding the cellular and molecular pathways of Nef action as well as the main characteristics of immune reconstitution following DOX withdrawal.

scholarly journals Human Immunodeficiency Virus Type 1 Vpr Impairs Dendritic Cell Maturation and T-Cell Activation: Implications for Viral Immune Escape

2005 ◽  
Vol 79 (13) ◽  
pp. 7990-8003 ◽  
Author(s):  
Biswanath Majumder ◽  
Michelle L. Janket ◽  
Elizabeth A. Schafer ◽  
Keri Schaubert ◽  
Xiao-Li Huang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
T Cell Activation ◽  
Immune Evasion ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Cytokine Profiling

ABSTRACT Antigen presentation and T-cell activation are dynamic processes involving signaling molecules present in both APCs and T cells. Effective APC function and T-cell activation can be compromised by viral immune evasion strategies, including those of human immunodeficiency virus type 1 (HIV-1). In this study, we determined the effects of HIV-1 Vpr on one of the initial target of the virus, dendritic cells (DC), by investigating DC maturation, cytokine profiling, and CD8-specific T-cell stimulation function followed by a second signal. Vpr impaired the expression of CD80, CD83, and CD86 at the transcriptional level without altering normal cellular transcription. Cytokine profiling indicated that the presence of Vpr inhibited production of interleukin 12 (IL-12) and upregulated IL-10, whereas IL-6 and IL-1β were unaltered. Furthermore, DC infected with HIV-1 vpr + significantly reduced the activation of antigen-specific memory and recall cytotoxic-T-lymphocyte responses. Taken together, these results indicate that HIV-1 Vpr may in part be responsible for HIV-1 immune evasion by inhibiting the maturation of costimulatory molecules and cytokines essential for immune activation.

scholarly journals Immune activation correlates with and predicts CXCR4 co-receptor tropism switch in HIV-1 infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bridgette J. Connell ◽  
Lucas E. Hermans ◽  
Annemarie M. J. Wensing ◽  
Ingrid Schellens ◽  
Pauline J. Schipper ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Causative Role ◽  
Subtype C ◽  
Subtype B ◽  
Hla Dr ◽  
Immunological Factors ◽  
Hiv 1

Abstract HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR+ CD4+ T-cells, %CD38+HLA-DR+ CD4+ T-cells, %CD38+HLA-DR+ CD8+ T-cells, %CD70+ CD4+ T-cells, %CD169+ monocytes, and absolute CD4+ T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003–1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR+ CD4+ T-cells, %HLA-DR+CD38+ CD4+ T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065–1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.

scholarly journals Processing and Presentation of Exogenous HLA Class I Peptides by Dendritic Cells from Human Immunodeficiency Virus Type 1-Infected Persons

2005 ◽  
Vol 79 (5) ◽  
pp. 3052-3062 ◽  
Author(s):  
Xiao-Li Huang ◽  
Zheng Fan ◽  
Bonnie A. Colleton ◽  
Rico Buchli ◽  
Hongyi Li ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Cell Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Dendritic cells (DCs) loaded with viral peptides are a potential form of immunotherapy of human immunodeficiency virus type 1 (HIV-1) infection. We show that DCs derived from blood monocytes of subjects with chronic HIV-1 infection on combination antiretroviral drug therapy have increases in expression of HLA, T-cell coreceptor, and T-cell activation molecules in response to the DC maturation factor CD40L comparable to those from uninfected persons. Mature DCs (mDCs) loaded with HLA A*0201-restricted viral peptides of the optimal length (9-mer) were more efficient at activating antiviral CD8+ T cells than were immature DCs or peptide alone. Optimal presentation of these exogenous peptides required uptake and vesicular trafficking and was comparable in DCs derived from HIV-1-infected and uninfected persons. Furthermore, DCs from HIV-1-infected and uninfected persons had similar capacities to process viral peptides with C-terminal and N-terminal extensions through their proteasomal and cytosolic pathways, respectively. We conclude that DCs derived from HIV-1-infected persons have similar abilities to process exogenous peptides for presentation to CD8+ T cells as those from uninfected persons. This conclusion supports the use of DCs loaded with synthetic peptides in immunotherapy of HIV-1 infection.

scholarly journals Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation

2018 ◽  
Vol 219 (7) ◽  
pp. 1084-1094 ◽  
Author(s):  
Eileen P Scully ◽  
Monica Gandhi ◽  
Rowena Johnston ◽  
Rebecca Hoh ◽  
Ainsley Lockhart ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Cell Activation ◽  
Immune Activation ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract Plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in women are lower early in untreated HIV-1 infection compared with those in men, but women have higher T-cell activation and faster disease progression when adjusted for viral load. It is not known whether these sex differences persist during effective antiretroviral therapy (ART), or whether they would be relevant for the evaluation and implementation of HIV-1 cure strategies. We prospectively enrolled a cohort of reproductive-aged women and matched men on suppressive ART and measured markers of HIV-1 persistence, residual virus activity, and immune activation. The frequency of CD4+ T cells harboring HIV-1 DNA was comparable between the sexes, but there was higher cell-associated HIV-1 RNA, higher plasma HIV-1 (single copy assay), and higher T-cell activation and PD-1 expression in men compared with women. These sex-related differences in immune phenotype and HIV-1 persistence on ART have significant implications for the design and measurement of curative interventions.

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