Liposome-encapsulated HIV-1 Gag p24 containing lipid A induces effector CD4+ T-cells, memory CD8+ T-cells, and pro-inflammatory cytokines

Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated in detail. Here, we studied the association of ART duration with memory subsets, exhaustion and metabolic profiles of CD8+ T cells from PLWH and improvement of polyfunctional and effector HIV-1 specific responses after stimulation with Gag-adjuvant-primed DC. HIV-1-specific CD8+ T cell responses from a larger proportion PLWH on ART for more than 10 years (LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, CD8+ T cells from PLWH on ART for less than a decade (ST-ARTp) were less responsive to DC treatment and functional improvement was limited in this group. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolytic induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.

Download Full-text

Faculty Opinions recommendation of Virtual memory CD8+ T cells restrain the viral reservoir in HIV-1-infected patients with antiretroviral therapy through derepressing KIR-mediated inhibition.

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

10.3410/f.737631829.793576112 ◽

2020 ◽

Author(s):

Sarah Rowland-Jones ◽

Ester Gea-Mallorqui

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Cd8 T Cells ◽

Virtual Memory ◽

Viral Reservoir ◽

Memory Cd8 T Cells ◽

Hiv 1

Download Full-text

CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway

Blood ◽

10.1182/blood.v96.1.195.013k51_195_202 ◽

2000 ◽

Vol 96 (1) ◽

pp. 195-202 ◽

Cited By ~ 1

Author(s):

Masaki Tateyama ◽

Naoki Oyaizu ◽

Thomas W. McCloskey ◽

Soe Than ◽

Savita Pahwa

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Interleukin 2 ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Cross Linking ◽

Induced Apoptosis ◽

Hiv 1

CD4 molecules serve as coreceptors for the T-cell receptor (TCR)/CD3 complex that are engaged coordinately with TCR and facilitate antigen-specific T-cell activation leading to interleukin 2 (IL-2) production and proliferation. However, cross-ligation of CD4 molecules prior to TCR stimulation has been shown to prime CD4 T cells to undergo apoptosis. Although in vivo and in vitro experiments have implicated the involvement of Fas/FasL interaction in this CD4 cross-linking (CD4XL)-induced apoptosis, detailed mechanisms to account for cell death induction have not been elucidated. In the present study, we demonstrate that CD4XL in purified T cells not only led to Fas up-regulation but also primed CD4 T cells to express FasL upon CD3 stimulation and rendered the T cells susceptible to Fas-mediated apoptosis. Notably, in addition to CD4+ T cells, CD4XL-induced sensitization for apoptosis was observed in CD8+ T cells as well and was associated with Bcl-x down-modulation. Both CD4 and CD8 T-cell subsets underwent apoptosis following cell–cell contact with FasL+ CD4 T cells. CD28 costimulation abrogated CD4XL/CD3-induced apoptosis with restoration of IL-2 production and prevented Bcl-x down-modulation. As CD4 molecules are the primary receptors for human immunodeficiency virus 1 (HIV-1), we conclude that HIV-1 envelope mediated CD4XL can lead to the generation of FasL-expressing CD4+ T cells that can lead to apoptosis of CD4 as well as CD8 T cells. These findings implicate a novel mechanism for CD8 T-cell depletion in HIV disease.

Download Full-text

Low Double-Negative CD3+CD4−CD8− T Cells Are Associated with Incomplete Restoration of CD4+ T Cells and Higher Immune Activation in HIV-1 Immunological Non-Responders

Frontiers in Immunology ◽

10.3389/fimmu.2016.00579 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Xiaofan Lu ◽

Bin Su ◽

Huan Xia ◽

Xin Zhang ◽

Zhiying Liu ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Activation ◽

Cd4 T Cells ◽

Double Negative ◽

Hiv 1

Download Full-text

Engineered Gag-specific T-cell Receptors Redirect Polyclonal CD8+ T-cells to Clear HIV-1-infected CD4+ T-cells from ART-treated Patients

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.5022.abstract ◽

2014 ◽

Vol 30 (S1) ◽

pp. A18-A18

Author(s):

Hongbing Yang ◽

Sandrine Buisson ◽

Giovanna Bossi ◽

Gemma Hancock ◽

Rebecca Ashfield ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Receptors ◽

Cd4 T Cells ◽

Cell Receptors ◽

Hiv 1

Download Full-text

Liposome-Coupled Peptides Induce Long-Lived Memory CD8+ T Cells Without CD4+ T Cells

PLoS ONE ◽

10.1371/journal.pone.0015091 ◽

2010 ◽

Vol 5 (11) ◽

pp. e15091 ◽

Cited By ~ 13

Author(s):

Maiko Taneichi ◽

Yuriko Tanaka ◽

Terutaka Kakiuchi ◽

Tetsuya Uchida

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Memory Cd8 T Cells

Download Full-text

Helios Expressing Regulatory T Cells are Correlated with Decreased IL-2 Producing CD8 T Cells and Antibody Diversity in Mozambican Individuals Living Chronically HIV-1

10.21203/rs.3.rs-778117/v1 ◽

2021 ◽

Author(s):

Raquel Matavele Chissumba ◽

Cacildo Magul ◽

Rosa Macamo ◽

Vânia Monteiro ◽

Maria Enosse ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Function ◽

Antibody Responses ◽

Virologic Suppression ◽

Antibody Diversity ◽

Immune Alterations ◽

Hiv 1

Abstract Background: Human immunodeficiency virus type 1 (HIV-1) causes impairment of T and B cell responses, which begins during the acute phase of infection and is not completely restored by antiretroviral treatment. Regulatory T cell (Tregs) can improve overall disease outcome by controlling chronic inflammation, but may also suppress beneficial HIV-1 specific immune responses. We analyzed immune alterations, including Tregs, and their clinical significance in Mozambican people living chronically with HIV-1 (PLWH-C). Results: In PLWH-C, the proportion of total Tregs was positively correlated with the proportion of IL-2+CD4 T cells (r=0.647; p=0.032) and IL-2+IFNg+CD8 T cells (r=0.551; p=0.014), while the Helios+Tregs correlated inversely with levels of IL-2+CD8 T cells (r= -0.541; p=0.017). Overall, PLWH-C, with (82%) or without virologic suppression (64%), were seronegative for at least HIV-1 p31, gp160 or p24, and the breadth of antibody responses was positively correlated with proportions of CD38+HLA-DR+CD8 T cells (r=0.620; p=0.012), viral load (r=0.452; p=0.040) and inversely CD4 T cells count (r=-0.481; p=0.027). Analysis of all individuals living HIV-1 showed that the breadth of HIV-1 antibody responses was inversely correlated with the proportion of Helios+Tregs (r=-0.45; p=0.02). Conclusion: Among Mozambican patients living with HIV-1, seronegativity to some HIV-1 proteins is common mostly in virologically suppressed individuals. Low diversity of HIV-specific antibodies is correlated to indicators of disease control during ART. Elevation in the proportion of Helios+Tregs is related to a reduction of CD8 T expressing intracellular IL-2 but may contribute to impairment of B cell function.

Download Full-text

Immunomodulatory Effects of Cyperus rotundus Extract on 7,12 Dimethylbenz[a]anthracene (DMBA) Exposed BALB/c Mice

Pharmaceutical Sciences ◽

10.34172/ps.2020.61 ◽

2020 ◽

Vol 27 (1) ◽

pp. 46-55

Author(s):

Abu Hanifah Ramadhani ◽

Wirdatun Nafisah ◽

Hary Isnanto ◽

Tri Kurniawati Sholeha ◽

Yoga Dwi Jatmiko ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Inflammatory Cytokines ◽

Cd8 T Cells ◽

Graphical Analysis ◽

Tumor Formation ◽

Cyperus Rotundus ◽

Carcinogenic Substance ◽

Activated T Lymphocytes ◽

Pro Inflammatory Cytokines

Background: The carcinogenic substance 7,12-Dimethylbenz[a]anthracene (DMBA) was commonly used to induce tumor formation in rodents. The development of tumor may trigger higher expression of pro-inflammatory cytokines, which in turn supports tumor progression. In this study, we examined the efficacy of Cyperus rotundus extract (CRE) that was reported to have anti-inflammatory properties. We focused on investigating the levels of activated T lymphocytes and the pro-inflammatory cytokines expressed by macrophages. Methods: Female BALB/c were injected with DMBA subcutaneously. The DMBA exposed mice were given CRE orally in three different doses; 63.33, 158.4, and 316.8 mg/kg. After 14 days, the levels of activated T lymphocytes and pro-inflammatory cytokines were analyzed using flow cytometry. Graphical analysis was done with FlowJo v10 and followed by statistical analysis. Results: The treatment of CRE reduced the population of CD4 and CD8 T cells. The number of activated CD4 and CD8 T cells were also significantly suppressed. The population of macrophages marked by CD11b cells was significantly reduced. Finally, the CRE treatment suppressed the levels of TNF-α, IFN-γ, IL-1β, and IL-6 expressed by macrophages. Conclusion: Our findings suggest that CRE could be a potential agent useful in therapeutic approaches for curing the disease caused by aberrant cells.

Download Full-text