Reduced Cellular Susceptibility to In Vitro HIV Infection Is Associated with CD4+ T Cell Quiescence

Purpose: Several observations suggest the presence of HIV-suppressive factors in the fluid phase of blood. Alpha-1-antitrypsin (AAT), the most abundant serine protease inhibitor in the circulation, has potent anti-HIV activity in vitro, and may function as an endogenous HIV suppressor. Therefore, we assessed serum AAT concentrations for association with HIV infection. Methods: In this cross-sectional study, serum AAT concentrations were measured in 66 persons with HIV infection and in 45 healthy persons (Controls). In the HIV-infected group, antiretroviral therapy (ART) use was assessed and CD4+ T cell levels and plasma HIV RNA were quantified. Results: Median AAT concentration was significantly lower in the HIV-infected group (1.64 mg/mL) in comparison with Controls (1.94 mg/mL; p=0.001). AAT reduction was most pronounced in the HIV-infected subgroup with CD4+ T cell levels > 200 cells/µL in comparison with Controls (p < 0.01). Serum AAT concentrations < 1.0 mg/mL are clinically significant, and concentrations below this level were identified in 4.5% of the HIV-infected group and in no Control subjects. No association between AAT levels and viral load or use of ART was observed in HIV-infected subjects. Conclusion: The association between reduced serum AAT concentration and HIV infection is consistent with a role for AAT as an endogenous HIV suppressor.

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Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections

Journal of Virology ◽

10.1128/jvi.01061-20 ◽

2020 ◽

Vol 94 (22) ◽

Author(s):

Sushant Khanal ◽

Qiyuan Tang ◽

Dechao Cao ◽

Juan Zhao ◽

Lam Nhat Nguyen ◽

...

Keyword(s):

Dna Damage ◽

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cell Apoptosis ◽

Cd4 T Cells ◽

Molecular Mechanisms ◽

Cd4 T Cell ◽

Cell Aging

ABSTRACT CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in vitro in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an in vitro HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection in vivo. We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This in vitro model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection. IMPORTANCE The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.

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Human Immunodeficiency Virus Type 1 Protease Inhibitor Modulates Activation of Peripheral Blood CD4+ T Cells and Decreases Their Susceptibility to Apoptosis In Vitro and In Vivo

Blood ◽

10.1182/blood.v94.3.1021.415k29_1021_1027 ◽

1999 ◽

Vol 94 (3) ◽

pp. 1021-1027 ◽

Cited By ~ 112

Author(s):

Elaine M. Sloand ◽

Princy N. Kumar ◽

Sonnie Kim ◽

Aniruddho Chaudhuri ◽

Frank F. Weichold ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Protease Inhibitor ◽

Protease Inhibitors ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cd4 Cells ◽

Immunodeficiency Virus

CD4+ T cells from patients with human immunodeficiency virus (HIV) infection undergo apoptosis at an increased rate, which leads to their depletion during disease progression. Both the Fas-Receptor (Fas-R) and interleukin-1β (IL-1β)–converting enzyme (ICE; caspase 1) appear to play a role in the mechanism of apoptosis of CD4+ lymphocytes. Although Fas-R is upregulated on both CD4+ and CD8+ cells in HIV-infected patients, results from our laboratory and others indicate that, in patients with advanced disease, CD4+ cells preferentially express ICE. Protease inhibitors have successfully halted the progression of HIV disease and increased CD4+ T counts. In this study, we examined the effect of protease inhibitors on Fas-R (CD95), ICE (caspase 1) expression, apoptosis, and cell death in CD4+ T cells of (1) HIV-infected patients who were receiving protease inhibitors, and (2) normal and patient CD4+ T cells cultured with a protease inhibitor in vitro. Fifteen patients with advanced HIV disease on treatment showed dramatically decreased CD4+ T-cell ICE expression, diminished apoptosis, and increased numbers of CD4+ cells within 6 weeks of institution of protease inhibitor therapy, and before down-modulation of Fas-R (CD95) expression was evident. To determine the role of HIV infection, we studied the effect of ritonavir, a protease inhibitor, on normal and patient cells in vitro. Stimulated and unstimulated normal CD4+ T cells, cultured with protease inhibitor, demonstrated markedly decreased apoptosis and ICE expression (P = .01). While Fas-R expression was not significantly altered during short-term culture by such treatment, Fas-Ligand (Fas-L) membrane expression of phytohemagglutinin (PHA)-stimulated blood lymphocytes was decreased by protease inhibitor. In the presence of ritonavir, CD4+ T cells from HIV-infected patients showed similar changes in ICE intracellular levels without alteration of Fas expression. In conclusion, protease inhibitors appear to decrease CD4+ T-cell ICE expression and apoptosis before they affect Fas-R expression in HIV-infected patients. This action was independent of HIV infection, as similar effects were seen in CD4+ T cells from normal controls. Some of the benefit of protease inhibitors may be related to modification of programmed cell death, which increases CD4+ T-cell number. Whether this is due to directly to the changes effected in the caspase system remains to be determined.

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Influence of cigarette-smoke extract conditioned medium on CD4+ T cell differentiation in vitro

Pneumologie ◽

10.1055/s-0033-1363104 ◽

2014 ◽

Vol 68 (02) ◽

Author(s):

N Baumgartl ◽

A Turowska ◽

H Garn

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Conditioned Medium ◽

Cigarette Smoke ◽

Cigarette Smoke Extract ◽

T Cell Differentiation ◽

Cd4 T Cell

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Monocyte-derived HLA-G, a strong inhibitor of autologous CD4 T-cell activation, is upregulated by interferon-β in vitro and in vivo: rationale for the therapy of multiple sclerosis?

Aktuelle Neurologie ◽

10.1055/s-2004-833324 ◽

2004 ◽

Vol 31 (S 1) ◽

Author(s):

M Mitsdörffer ◽

B Schreiner ◽

BC Kieseier ◽

O Neuhaus ◽

J Dichgans ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Interferon Β ◽

Strong Inhibitor

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Faculty Opinions recommendation of CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause?

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

10.3410/f.1005553.65907 ◽

2002 ◽

Author(s):

John Moore

Keyword(s):

T Cell ◽

Hiv Infection ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion

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Faculty Opinions recommendation of Central memory CD4+ T cell responses in chronic HIV infection are not restored by antiretroviral therapy.

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

10.3410/f.1020334.233434 ◽

2004 ◽

Author(s):

Luis J Montaner

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

T Cell Responses ◽

Central Memory ◽

Cd4 T Cell ◽

Cell Responses ◽

Chronic Hiv Infection

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Faculty Opinions recommendation of Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.

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

10.3410/f.7582957.9635054 ◽

2011 ◽

Author(s):

Andrew Badley ◽

Nathan Cummins

Keyword(s):

T Cell ◽

Hiv Infection ◽

Lymphoid Tissue ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion ◽

Human Lymphoid Tissue

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The Effect of Antiretroviral Therapy on IL-6, IL-1β, TNF-α, IFN-γ Levels and their Relationship with HIV-RNA and CD4+ T Cells in HIV Patients

Current HIV Research ◽

10.2174/1570162x18666200712174642 ◽

2020 ◽

Vol 18 (5) ◽

pp. 354-361

Author(s):

Gülay Okay ◽

Meliha Meric Koc ◽

Eray Metin Guler ◽

Ayşegül Yabaci ◽

Abdürrahim Kocyigit ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Cell Count ◽

Cd4 T Cell ◽

Positive Correlation ◽

Hiv Rna ◽

Tnf Α ◽

Cytokine Levels ◽

Ifn Γ ◽

Cd4 T Cell Count

Background: Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART). Objectives: The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels. Methods: The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls. Results: The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00). Conclusions: Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection.

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