Disruption of the HPA axis through down-regulation of glucocorticoid receptor expression in T cells of HIV-1-infected patients as a mechanism of chronic immune activation

HIV infection results in a state of chronic immune activation leading to premature immune aging, B-cells dysfunction, that persists despite prolonged virological suppression. In this scenario, adolescence living with perinatally acquired HIV (PHIV), deserve a peculiar attention since potentially exposed for their entire life to chronic immune activation. Here we identified determinants of precocious aging B cells in 40 PHIV undergoing suppressive antiretroviral therapy (ART) for median 13.5 years. All individuals started ART by 2 nd year of life and achieved virus suppression within the 1 st year of ART, with majority of patient maintaining suppression until analysis and 5/40 experiencing viral Spike (transient elevation of HIV-1 VL, 50-999 copies/ml). We employed a multi-omics approach including deep immunological B and T cell phenotype in PBMC, with aging B cells defined by the expression of T-bet and CD11c; plasma proteomics analysis by mass spectrometry and serum level of anti-measles antibodies as correlates of humoral response. We found that individuals with expansion of aging B cell, defined by the expression of T-bet+CD11c+, were those starting treatment later, presenting detectable levels of cell-associated HIV-1 RNA, history of Spikes, and a higher frequency of exhausted T-cells, including those expressing PD-1, LAG3, TIGIT. Accordingly, the proteomic analysis revealed that subjects with expansion of aging B cells and exhausted T cells had enrichment of proteins involved in immune inflammation and complement activation pathways, such as CLU and APCS which are also involved in tumor progression. Signs of precocious aging were associated with a reduced capacity to maintain virological memory against measles vaccination. To our knowledge, this is the first study focusing on precocious B-cell aging and dysfunctionality in PHIV with long-term virological suppression. Our experimental strategy enabled identification of clinical, viral, cellular and plasma soluble markers associated with B-cells aging. Our results pave the way to further define risk of disease progression or lymphoproliferative disorders in PHIV.

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Regulatory T cells and chronic immune activation in human immunodeficiency virus 1 (HIV-1)-infected children

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2011.04383.x ◽

2011 ◽

Vol 164 (3) ◽

pp. 373-380 ◽

Cited By ~ 25

Author(s):

R. Freguja ◽

K. Gianesin ◽

I. Mosconi ◽

M. Zanchetta ◽

F. Carmona ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Regulatory T Cells ◽

Immune Activation ◽

Chronic Immune Activation ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Human Immunodeficiency Virus 1

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High Levels of Chronic Immune Activation in the T-Cell Compartments of Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Type 1 and on Highly Active Antiretroviral Therapy Are Reverted by Alpha Interferon and Ribavirin Treatment

Journal of Virology ◽

10.1128/jvi.01211-09 ◽

2009 ◽

Vol 83 (21) ◽

pp. 11407-11411 ◽

Cited By ~ 103

Author(s):

Veronica D. Gonzalez ◽

Karolin Falconer ◽

Kim G. Blom ◽

Olle Reichard ◽

Birgitte Mørn ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Antiretroviral Therapy ◽

Immune Activation ◽

Chronic Immune Activation ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Chronic immune activation is a driver of human immunodeficiency virus type 1 (HIV-1) disease progression. Here, we describe that subjects with chronic hepatitis C virus (HCV)/HIV-1 coinfection display sharply elevated immune activation as determined by CD38 expression in T cells. This occurs, despite effective antiretroviral therapy, in both CD8 and CD4 T cells and is more pronounced than in the appropriate monoinfected control groups. Interestingly, the suppression of HCV by pegylated alpha interferon and ribavirin treatment reduces activation. High HCV loads and elevated levels of chronic immune activation may contribute to the high rates of viral disease progression observed in HCV/HIV-1-coinfected patients.

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Vitamin D decreasesin vitroglucocorticoid sensitivity via down regulation of glucocorticoid receptor expression

Endocrine Abstracts ◽

10.1530/endoabs.37.oc5.2 ◽

2015 ◽

Author(s):

Narjes Nasiri Ansari ◽

Eliana Spilioti ◽

Vasiliki Kalotychou ◽

Geena Dalagiorgou ◽

Paraskevi Moutsatsou ◽

...

Keyword(s):

Vitamin D ◽

Glucocorticoid Receptor ◽

Receptor Expression ◽

Down Regulation

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Human Endogenous Retrovirus Expression Is Inversely Associated with Chronic Immune Activation in HIV-1 Infection

PLoS ONE ◽

10.1371/journal.pone.0041021 ◽

2012 ◽

Vol 7 (8) ◽

pp. e41021 ◽

Cited By ~ 19

Author(s):

Christopher E. Ormsby ◽

Devi SenGupta ◽

Ravi Tandon ◽

Steven G. Deeks ◽

Jeffrey N. Martin ◽

...

Keyword(s):

Immune Activation ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Chronic Immune Activation ◽

Hiv 1

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Spontaneous HCV clearance in HCV/HIV-1 coinfection associated with normalized CD4 counts, low level of chronic immune activation and high level of T cell function

Journal of Clinical Virology ◽

10.1016/j.jcv.2007.11.005 ◽

2008 ◽

Vol 41 (2) ◽

pp. 160-163 ◽

Cited By ~ 23

Author(s):

Karolin Falconer ◽

Veronica D. Gonzalez ◽

Olle Reichard ◽

Johan K. Sandberg ◽

Annette Alaeus

Keyword(s):

T Cell ◽

Immune Activation ◽

Cell Function ◽

Chronic Immune Activation ◽

Cd4 Counts ◽

Low Level ◽

T Cell Function ◽

Spontaneous Hcv Clearance ◽

High Level ◽

Hiv 1

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Limited expression of R5-tropic HIV-1 in CCR5-positive type 1–polarized T cells explained by their ability to produce RANTES, MIP-1α, and MIP-1β

Blood ◽

10.1182/blood.v95.4.1167.004k11_1167_1174 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1167-1174 ◽

Cited By ~ 37

Author(s):

Francesco Annunziato ◽

Grazia Galli ◽

Filomena Nappi ◽

Lorenzo Cosmi ◽

Roberto Manetti ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Receptor Expression ◽

Th2 Cells ◽

Th1 Cells ◽

Naive T Cells ◽

Naïve T Cells ◽

Viral Spread ◽

Hiv 1

Human T helper (Th) cells (Th1- or Th2-oriented memory T cells as well as Th1- or Th2-polarized naive T cells) were infected in vitro with an R5-tropic HIV-1 strain (BaL) and assessed for their profile of cytokine production, CCR5 receptor expression, and HIV-1 p24 antigen (p24 Ag) production. Higher p24 Ag production was found in CCR5-negative Th2-like memory T cells than in CCR5-positive Th1-like memory T cells. By contrast, p24 Ag production was higher in Th1-polarized activated naive T cells in the first 4 days after infection. However, p24 Ag production in Th1-polarized T cells became comparable or even lower than the production in Th2-polarized populations later in infection or when the cells were infected with HIV-1BaL after secondary stimulation. The higher levels of p24 Ag production by Th1-polarized naive T cells soon after infection reflected a higher virus entry, as assessed by the single round infection assay using the HIV–chloramphenicol acetyl transferase (HIV-CAT) R5-tropic virus that contains the envelope protein of HIV-1 YU2 strain. The limitation of viral spread in the Th1-polarized populations, despite the initial higher level of T-cell entry of R5-tropic strains, was due to the ability of Th1 cells to produce greater amounts of β-chemokines than Th2 cells. In fact, an inverse correlation was observed between Th1-polarized naive T cells and Th1-like memory-activated T cells in regards to p24 Ag production and the release of the following CCR5-binding chemokines: regulated on activation normal T expressed and secreted (RANTES), macrophage inflammatory protein–1 (MIP-1), and MIP-1β. Moreover, infection with the HIV-1BaL strain of Th1-polarized T cells in the presence of a mixture of anti-RANTES, anti–MIP-1, and anti–MIP-1β neutralizing antibodies resulted in a significant increase of HIV-1 expression. These findings suggest that Th1-type responses may favor CD4+ T-cell infection by R5-tropic HIV-1 strains, but HIV-1 spread in Th1 cells is limited by their ability to produce CCR5-binding chemokines.

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Vδ1 T lymphocytes producing IFN-γ and IL-17 are expanded in HIV-1–infected patients and respond to Candida albicans

Blood ◽

10.1182/blood-2009-01-198028 ◽

2009 ◽

Vol 113 (26) ◽

pp. 6611-6618 ◽

Cited By ~ 112

Author(s):

Daniela Fenoglio ◽

Alessandro Poggi ◽

Silvia Catellani ◽

Florinda Battaglia ◽

Alessandra Ferrera ◽

...

Keyword(s):

T Cells ◽

Candida Albicans ◽

T Cell ◽

T Lymphocytes ◽

Receptor Expression ◽

Interleukin 17 ◽

Γδ T Cell ◽

Healthy Donors ◽

Ifn Γ ◽

Hiv 1

AbstractIn early HIV-1 infection, Vδ1 T lymphocytes are increased in peripheral blood and this is related to chemokine receptor expression, chemokine response, and recirculation. Herein we show that, at variance with healthy donors, in HIV-1–infected patients ex vivo–isolated Vδ1 T cells display cytoplasmic interferon-γ (IFN-γ). Interestingly, these cells coexpress cytoplasmic interleukin-17 (IL-17), and bear the CD27 surface marker of the memory T-cell subset. Vδ1 T cells, isolated from either patients or healthy donors, can proliferate and produce IFN-γ and IL-17 in response to Candida albicans in vitro, whereas Vδ2 T cells respond with proliferation and IFN-γ/IL-17 production to mycobacterial or phosphate antigens. These IFN-γ/IL-17 double-producer γδ T cells express the Th17 RORC and the Th1 TXB21 transcription factors and bear the CCR7 homing receptor and the CD161 molecule that are involved in γδ T-cell transendothelial migration. Moreover, Vδ1 T cells responding to C albicans express the chemokine receptors CCR4 and CCR6. This specifically equipped circulating memory γδ T-cell population might play an important role in the control of HIV-1 spreading and in the defense against opportunistic infections, possibly contributing to compensate for the impairment of CD4+ T cells.

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