scholarly journals Pharmacological Inhibition of PPARy Boosts HIV Reactivation and Th17 Effector Functions, while Preventing Progeny Virion Release and de novo Infection

2020 ◽  
Vol 5 (1) ◽  
pp. 177
Author(s):  
Delphine Planas ◽  
Augustine Fert ◽  
Yuwei Zhang ◽  
Jean-Philippe Goulet ◽  
Jonathan Richard ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
People Living With Hiv ◽  
Hiv Reservoir ◽  
Effector Functions ◽  
Pharmacological Inhibition ◽  
Hiv Transcription ◽  
Virion Release ◽  
Progeny Virion

The frequency and functions of Th17-polarized CCR6+RORyt+CD4+ T cells are rapidly compromised upon HIV infection and are not restored with long-term viral suppressive antiretroviral therapy (ART). In line with this, Th17 cells represent selective HIV-1 infection targets mainly at mucosal sites, with long-lived Th17 subsets carrying replication-competent HIV-DNA during ART. Therefore, novel Th17-specific therapeutic interventions are needed as a supplement of ART to reach the goal of HIV remission/cure. Th17 cells express high levels of peroxisome proliferator-activated receptor gamma (PPARy), a transcriptional factor that represses the transcription of the HIV provirus and the rorc gene, which encodes for the Th17-specific master regulator RORyt/RORC2. Thus, we hypothesized that the pharmacological inhibition of PPARy will facilitate HIV reservoir reactivation while enhancing Th17 effector functions. Consistent with this prediction, the PPARy antagonist T0070907 significantly increased HIV transcription (cell-associated HIV-RNA) and RORyt-mediated Th17 effector functions (IL-17A). Unexpectedly, the PPARy antagonism limited HIV outgrowth from cells of ART-treated people living with HIV (PLWH), as well as HIV replication in vitro. Mechanistically, PPARy inhibition in CCR6+CD4+ T cells induced the upregulation of transcripts linked to Th17-polarisation (RORyt, STAT3, BCL6 IL-17A/F, IL-21) and HIV transcription (NCOA1-3, CDK9, HTATIP2). Interestingly, several transcripts involved in HIV-restriction were upregulated (Caveolin-1, TRIM22, TRIM5α, BST2, miR-29), whereas HIV permissiveness transcripts were downregulated (CCR5, furin), consistent with the decrease in HIV outgrowth/replication. Finally, PPARy inhibition increased intracellular HIV-p24 expression and prevented BST-2 downregulation on infected T cells, suggesting that progeny virion release is restricted by BST-2-dependent mechanisms. These results provide a strong rationale for considering PPARy antagonism as a novel strategy for HIV-reservoir purging and restoring Th17-mediated mucosal immunity in ART-treated PLWH.

scholarly journals Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling

2013 ◽  
Vol 210 (7) ◽  
pp. 1433-1445 ◽  
Author(s):  
Nataša Obermajer ◽  
Jeffrey L. Wong ◽  
Robert P. Edwards ◽  
Kong Chen ◽  
Melanie Scott ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
De Novo ◽  
Inflammatory Diseases ◽  
Suppressor Cells ◽  
Guanosine Monophosphate ◽  
No Production ◽  
No Signaling

Nitric oxide (NO) is a ubiquitous mediator of inflammation and immunity, involved in the pathogenesis and control of infectious diseases, autoimmunity, and cancer. We observed that the expression of nitric oxide synthase-2 (NOS2/iNOS) positively correlates with Th17 responses in patients with ovarian cancer (OvCa). Although high concentrations of exogenous NO indiscriminately suppress the proliferation and differentiation of Th1, Th2, and Th17 cells, the physiological NO concentrations produced by patients’ myeloid-derived suppressor cells (MDSCs) support the development of RORγt(Rorc)+IL-23R+IL-17+ Th17 cells. Moreover, the development of Th17 cells from naive-, memory-, or tumor-infiltrating CD4+ T cells, driven by IL-1β/IL-6/IL-23/NO-producing MDSCs or by recombinant cytokines (IL-1β/IL-6/IL-23), is associated with the induction of endogenous NOS2 and NO production, and critically depends on NOS2 activity and the canonical cyclic guanosine monophosphate (cGMP)–cGMP-dependent protein kinase (cGK) pathway of NO signaling within CD4+ T cells. Inhibition of NOS2 or cGMP–cGK signaling abolishes the de novo induction of Th17 cells and selectively suppresses IL-17 production by established Th17 cells isolated from OvCa patients. Our data indicate that, apart from its previously recognized role as an effector mediator of Th17-associated inflammation, NO is also critically required for the induction and stability of human Th17 responses, providing new targets to manipulate Th17 responses in cancer, autoimmunity, and inflammatory diseases.

Sarcopenic obesity is associated with lower frequency of CD4+ T cells and high prevalence of metabolic syndrome in people living with HIV

2018 ◽  
Vol 37 ◽  
pp. S21
Author(s):  
I.A. Osuna Padilla ◽  
A. Aguilar Vargas ◽  
A. Villazon de la Rosa ◽  
N.C. Rodriguez Moguel ◽  
Y. Vargas Infante ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
T Cells ◽  
Cd4 T Cells ◽  
Sarcopenic Obesity ◽  
People Living With Hiv ◽  
High Prevalence ◽  
Living With Hiv

scholarly journals ABX464 decreases the total HIV reservoir and HIV transcription initiation in CD4 + T cells from HIV-infected ART-suppressed individuals

2021 ◽  
Author(s):  
Sara Moron-Lopez ◽  
Silvia Bernal ◽  
Joseph K Wong ◽  
Javier Martinez-Picado ◽  
Steven A Yukl
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Transcription Initiation ◽  
Digital Pcr ◽  
Fold Change ◽  
Hiv Rna ◽  
Hiv Transcription ◽  
Hiv Dna ◽  
Median Level ◽  
Term Administration

Abstract Background Antiretroviral therapy (ART) intensification and disruption of latency have been suggested as strategies to eradicate HIV. ABX464 is a novel antiviral that inhibits HIV RNA biogenesis. We investigated the effect of ABX464 on HIV transcription and total and intact HIV DNA in CD4 + T cells from ART-suppressed participants enrolled in the ABIVAX-005 clinical trial (NCT02990325). Methods Peripheral CD4 + T cells were available for analysis from nine ART-suppressed participants who were treated daily with 150mg of ABX464 for 4 weeks. Total and intact HIV DNA, and initiated, 5’elongated, unspliced, polyadenylated and multiply-spliced HIV transcripts, were quantified at weeks 0, 4 and 8 using droplet digital PCR. Results We observed a significant decrease in total HIV DNA (p=0.008, median fold-change=0.8) and a lower median level of intact HIV DNA (p=n.s., median fold-change=0.8) after ABX464 treatment (wk 0 vs. 4). Moreover, we observed a decrease in initiated HIV RNA per million CD4 + T cells and per provirus (p=0.05, median fold-change=0.7; p=0.004, median fold-change=0.5, respectively), a trend towards a decrease in the 5’elongated HIV RNA per provirus (p=0.07, median fold-change=0.5), and a lower median level of unspliced HIV RNA (p=n.s., median fold-change=0.6), but no decrease in polyadenylated or multiply-spliced HIV RNA. Conclusion In this substudy, ABX464 had a dual effect of decreasing total HIV DNA (and possibly intact proviruses) and decreasing the amount of HIV transcription per provirus. To further characterize its specific mechanism of inhibiting HIV transcription, long-term administration of ABX464 should be studied in a larger cohort.

scholarly journals Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells

2013 ◽  
Vol 190 (11) ◽  
pp. 5788-5798 ◽  
Author(s):  
Takeshi Kawabe ◽  
Shu-lan Sun ◽  
Tsuyoshi Fujita ◽  
Satoshi Yamaki ◽  
Atsuko Asao ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Homeostatic Proliferation ◽  
Mesenteric Lymph Nodes ◽  
Mesenteric Lymph

scholarly journals OA1-2 Enrichment of the HIV reservoir in CD32 + CD4 T cells occurs early and is closely associated with immune checkpoint receptor expression

2017 ◽  
Vol 3 ◽  
pp. 1-2
Author(s):  
G.E. Martin ◽  
M. Pace ◽  
J.P. Thornhill ◽  
C. Phetsouphanh ◽  
E. Hopkins ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Receptor Expression ◽  
Hiv Reservoir

Flow Cytometry Sorting of Memory CCR6+CD4+ T-Cells for HIV Reservoir Quantification

2022 ◽  
pp. 81-89
Author(s):  
Amélie Cattin ◽  
Augustine Fert ◽  
Delphine Planas ◽  
Petronela Ancuta
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cd4 T Cells ◽  
Hiv Reservoir ◽  
Flow Cytometry Sorting

scholarly journals Impact of the level of pre-ART CD4+ T cells in blood on the rectal HIV reservoir in long-term treated men (VIRECT study)

2014 ◽  
Vol 14 (S2) ◽  
Author(s):  
Delphine Vergnon-Miszczycha ◽  
Alexandre Girard ◽  
Anne Depincé ◽  
Xavier Roblin ◽  
Emilie Del Tedesco ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Hiv Reservoir

scholarly journals An Assessment of Malaria Parasite Density among HIV/AIDS-Subjects at Different Levels of CD4 T-Cells Prior to Antimalarial Therapy at Chulaimbo Sub-County Hospital, Western Kenya

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
J. K. Kirinyet
Keyword(s):  
T Cells ◽  
Parasite Density ◽  
Cd4 T Cells ◽  
Malaria Parasite ◽  
People Living With Hiv ◽  
Western Kenya ◽  
Geometrical Mean ◽  
Sub Saharan ◽  
Living With Hiv ◽  
Hiv Aids

Background. Malaria and HIV/AIDS infections are among the major public health concerns in sub-Saharan Africa, where they are associated with high morbidity and mortality. Recent findings indicate that individual people living with HIV/AIDS (PLWHA) with lower levels of CD4 T-cell count below 200/mm3 tend to experience higher mean malaria parasite densities than their counterparts with higher CD4 T-cells counts. Aim. The study was conducted to assess the pattern of malaria parasite density at different levels of CD4 T-cells among people living with HIV/AIDS in Western part of Kenya. Subjects and Methods. A randomized antimalarial treatment study among 126 people living with HIV/AIDS was conducted at Chulaimbo Sub-County Hospital, Western Kenya. All the participants enrolled into the study had their blood samples assessed for malaria parasite densities before commencement of antimalarial therapy and the results correlated with their CD4 T-cells levels obtained from their respective files. Results. Mean malaria parasite density on pretreatment samples was 43,168 parasites /μL of blood, median was 17,720, and mode was 4,000. Male participants had a higher geometrical mean parasite density (26,424) compared to females’ (15,346) (p = 0.03). Low CD4 counts were associated with high density malaria parasitaemia and consequently, very high CD4 counts seemed to exhibit low malaria parasite density among PLWHA. An insignificant negative correlation, however, between CD4 T-cells count and malaria parasite densities was noted (p = 0.169). Conclusion. The study was able to establish higher parasite density among individuals with ≤200 cells/μL than their counterparts with >200 cells/μL of CD4 T-cell levels in PLWHA resident in Western Kenya. Secondly, males significantly had a higher geometrical mean parasite density than females regardless of their CD4 status. It is anticipated that the results from this study could be used/applied in developing interventional measures to address malaria/HIV-AIDS coinfections aimed at saving life, particularly in the sub-Saharan African region where the two infections are rampant.

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