CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis

ABSTRACT Apoptosis of peripheral blood T cells plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 (HIV-1) primes CD4+ T cells from healthy donors for apoptosis, which occurs after CD95 ligation or CD3-T-cell receptor (TCR) stimulation. CD95-mediated death did not depend on CD4 T-cell infection, since it occurred in the presence of the reverse transcriptase inhibitor didanosine (ddI). In contrast, apoptosis induced by productive infection (CD3-TCR stimulation) is prevented by both CD95 decoy receptor and ddI. Our data suggest that HIV-1 triggers at least two distinct death pathways: a CD95-dependent pathway that does not require viral replication and a viral replication-mediated cell death independent of the CD95 pathway. Further experiments indicated that saquinavir, a protease inhibitor, at a 0.2 μM concentration, decreased HIV-mediated CD95 expression and thus cell death, which is independent of its role in inhibiting viral replication. However, treatment of peripheral blood mononuclear cells from healthy donors with a higher concentration (10 μM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (ΔΨm) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4+ T cells independent of their antiretroviral effects.

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Faculty Opinions recommendation of Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718214298.793491069 ◽

2014 ◽

Author(s):

Vincent Emery

Keyword(s):

Cell Death ◽

T Cell ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion ◽

Hiv 1

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Growth of macrophage-tropic and primary human immunodeficiency virus type 1 (HIV-1) isolates in a unique CD4+ T-cell clone (PM1): failure to downregulate CD4 and to interfere with cell-line-tropic HIV-1.

Journal of Virology ◽

10.1128/jvi.69.6.3712-3720.1995 ◽

1995 ◽

Vol 69 (6) ◽

pp. 3712-3720 ◽

Cited By ~ 183

Author(s):

P Lusso ◽

F Cocchi ◽

C Balotta ◽

P D Markham ◽

A Louie ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Cell Line ◽

Human Immunodeficiency Virus Type ◽

Cell Clone ◽

Cd4 T Cell ◽

T Cell Clone ◽

Immunodeficiency Virus ◽

Hiv 1

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Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death

Journal of Virology ◽

10.1128/jvi.79.5.3195-3199.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 3195-3199 ◽

Cited By ~ 15

Author(s):

Jean-Daniel Lelièvre ◽

Frédéric Petit ◽

Damien Arnoult ◽

Jean-Claude Ameisen ◽

Jérôme Estaquier

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Hiv Infection ◽

Cell Infection ◽

Interleukin 7 ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Fas-mediated T-cell death is known to occur during human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 LAI (HIV-1LAI) primes CD8+ T cells from healthy donors for apoptosis, which occurs after Fas ligation. This effect is counteracted by a broad caspase inhibitor (zVAD-fmk). Fas-mediated cell death does not depend on CD8+ T-cell infection, because it occurred in the presence of reverse transcriptase inhibitors. However, purified CD8+ T cells are sensitive to Fas only in the presence of soluble CD4. Finally, we found that interleukin 7 (IL-7) increases Fas-mediated CD4+ and CD8+ T-cell death induced by HIV-1LAI. Since high levels of IL-7 are a marker of poor prognosis during HIV infection, our data suggest that enhancement of Fas-mediated T-cell death by HIV-1LAI and IL-7 is one of the mechanisms involved in progression to AIDS.

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HIV-specific T-cell Responses and Generalized Activation in HIV-1 Infected Long-term Non-progressors and Progressors from South India

Current HIV Research ◽

10.2174/1570162x17666181212122607 ◽

2019 ◽

Vol 16 (4) ◽

pp. 302-314

Author(s):

Chinnambedu Ravichandran Swathirajan ◽

Ramachandran Vignesh ◽

Greer Waldrop ◽

Uma Shanmugasundaram ◽

Pannerselvam Nandagopal ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Cell Responses ◽

Activation Rates ◽

Hiv 1

Background:Anti-viral cytokine expressions by cytotoxic T-cells and lower activation rates have been reported to correlate with suppressed HIV replication in long-term non-progressors (LTNP). Immune mechanisms underlying disease non-progression in LTNP might vary with HIV-1 subtype and geographical locations.Objective:This study evaluates cytokine expression and T-cells activation in relation to disease non-progression in LTNP.Methods:HIV-1 Subtype C infected LTNP (n=20) and progressors (n=15) were enrolled and flowcytometry assays were performed to study HIV-specific CD8 T-cells expressing IL-2, IFN-γ, TNF-α and MIP-1β against gag and env peptides. CD4+ T-cell activation was evaluated by surface expression of HLADR and CD38.Results:Proportions of cytokines studied did not differ significantly between LTNP and progressors, while contrasting correlations with disease progression markers were observed in LTNP. CD4+ T-cell activation rates were significantly lower in LTNP compared to progressors which indicate the potential role of T-cell activation rates in disease non-progression in LTNP.Conclusion:LTNP and progressors showed similar CD8+ T-cell responses, but final conclusions can be drawn only by comparing multiple immune factors in larger LTNP cohort with HIV-1 infected individuals at various levels of disease progression. A possible role of HIV-1 subtype variation and ethnic differences in addition to host-genetic and viral factors cannot be ruled out.

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The role of upstream U3 sequences in HIV-1 replication and CD4+ T cell depletion in human lymphoid tissue ex vivo

Virology ◽

10.1016/j.virol.2005.07.023 ◽

2005 ◽

Vol 341 (2) ◽

pp. 313-320 ◽

Cited By ~ 8

Author(s):

Jan Münch ◽

Devi Rajan ◽

Elke Rücker ◽

Steffen Wildum ◽

Nadia Adam ◽

...

Keyword(s):

T Cell ◽

Lymphoid Tissue ◽

Ex Vivo ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion ◽

Human Lymphoid Tissue ◽

Hiv 1

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Role of HIV-1 phenotype in viral pathogenesis and its relation to viral load and CD4+ T-cell count

Journal of Medical Virology ◽

10.1002/(sici)1096-9071(199811)56:3<259::aid-jmv14>3.0.co;2-9 ◽

1998 ◽

Vol 56 (3) ◽

pp. 259-263 ◽

Cited By ~ 9

Author(s):

Bernd Kupfer ◽

Rolf Kaiser ◽

Jürgen Kurt Rockstroh ◽

Bertfried Matz ◽

Karl Eduard Schneweis

Keyword(s):

Viral Load ◽

T Cell ◽

Cell Count ◽

Viral Pathogenesis ◽

Cd4 T Cell ◽

Hiv 1 ◽

Cd4 T Cell Count

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Entry and Transcription as Key Determinants of Differences in CD4 T-Cell Permissiveness to Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.78.19.10747-10754.2004 ◽

2004 ◽

Vol 78 (19) ◽

pp. 10747-10754 ◽

Cited By ~ 31

Author(s):

Angela Ciuffi ◽

Gabriela Bleiber ◽

Miguel Muñoz ◽

Raquel Martinez ◽

Corinne Loeuillet ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Virus Production ◽

Cd4 T Cell ◽

Total Variance ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Isolated primary human cells from different donors vary in their permissiveness—the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4+ CD45RO+ CD57− T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.

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Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals

Blood ◽

10.1182/blood.v82.11.3392.bloodjournal82113392 ◽

1993 ◽

Vol 82 (11) ◽

pp. 3392-3400 ◽

Cited By ~ 2

Author(s):

N Oyaizu ◽

TW McCloskey ◽

M Coronesi ◽

N Chirmule ◽

VS Kalyanaraman ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Mononuclear Cells ◽

Cross Linking ◽

Peripheral Blood Mononuclear ◽

Immunodeficiency Virus ◽

Blood Mononuclear Cells ◽

Hiv 1

This study investigates apoptosis as a mechanism for CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1) infection. Although several recent studies have shown that T cells of HIV-infected individuals show enhanced susceptibility to cell death by apoptosis, the mechanisms responsible for apoptosis are largely unknown. By using a flow cytometric technique and by morphology, we have quantitated the percentage of cells undergoing apoptosis in peripheral blood mononuclear cells (PBMCs) from HIV-seronegative donors and from HIV- infected asymptomatic patients. The PBMCs were cultured without any stimulus or with staphylococcus enterotoxin B, anti-T-cell receptor (TCR) alpha beta monoclonal antibody WT-31, or phytohemagglutinin for periods up to 6 days. In addition, we sought to determine whether cross- linking of CD4 followed by various modes of TCR stimulation in vitro could induce apoptosis in normal PBMCs. Here we show that (1) patient PMBCs undergo marked spontaneous apoptosis; (2) stimulation of T cells of patients as well as normal donors results in increased apoptosis; and (3) cross-linking of CD4 molecules is sufficient to induce apoptosis in CD4+ T cells if cross-linking is performed in unfractioned PBMCs, but not if CD4 molecules are cross-linked in purified T-cell preparations. These observations strongly suggest that accelerated cell death through apoptosis plays an important role in the pathogenesis of HIV-1 infection. At the same time, our observations implicate cross- linking of CD4 in vivo as a major contributor to this mechanism of accelerated cell death in HIV infection.

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