Antiretroviral therapy-treated HIV-infected adults with coronary artery disease are characterized by a distinctive regulatory T-cell signature

Rothan, Céline; Yero, Alexis; Shi, Tao; Farnós, Omar; Chartrand-Lefèbvre, Carl; El‐Far, Mohamed; Costiniuk, Cecilia T.; Tsoukas, Christos; Tremblay, Cécile; Durand, Madéleine; Jenabian, Mohammad-Ali

doi:10.1097/qad.0000000000002842

Cited by 11 publications

(14 citation statements)

References 56 publications

(112 reference statements)

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“…Thus, by having not only MZp, but also mature MZ expressing lower levels of CD39 and CD73, HIV+ CVD+ individuals are possibly burdened with higher inflammation levels than the other groups, likely contributing to early atherosclerosis development. Importantly, the loss of CD39 and CD73 has also been reported in regulatory T-cells of HIV+ CVD+ individuals of the CHACS cohort, further demonstrating the possible link between deregulations of the adenosine pathway and atherosclerosis [55].…”

Section: Discussionmentioning

confidence: 97%

Subclinical Atherosclerosis is Associated with Discrepancies in BAFF and APRIL Levels and Altered Breg Potential of Precursor-like Marginal Zone B-Cells in HIV Treated Individuals

Aranguren

Doyon-Laliberté

El‐Far

et al. 2022

Preprint

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Chronic inflammation persists in people living with HIV (PLHIV) despite antiretrovial therapy (ART), and is involved in their premature development of cardiovascular diseases (CVD) such as atherosclerosis. We have previously reported that an excess of "B-cell activating factor" (BAFF), an important molecule for the selection and activation of first line Marginal Zone (MZ) B-cell populations, is associated with deregulations of precursor-like MZ (MZp), whose potent B-cell regulatory (Breg) capacities are altered in PLHIV, early on and despite 1-2 years of ART. Based on these observations, and growing evidence that MZ populations are involved in atherosclerosis control, we designed a cross sectional study to explore the associations between BAFF and its analogue "A proliferation-inducing ligand" (APRIL) with subclinical CVD in long time treated individuals of the Canadian HIV and Aging Cohort Study (CHACS) imaging sub-study group. We also characterized the Breg profile of MZp from the blood of these individuals. Results were correlated with the total volume of atherosclerotic plaques (TPV) and with CVD risk factors and biomarkers. TPV was measured using cardiac computerised tomography angiography, and presence of CVD was defined as TPV > 0. We report that blood levels of BAFF are elevated and correlate positively with CVD and its risk factors in PLHIV from the CHACS, in contrast to APRIL levels, which correlate negatively with these factors. Expression levels of Breg markers such as NR4A3, CD39, CD73 and CD83 are significantly lower in PLHIV when compared to those of HIV-uninfected controls. In vitro experiments show that APRIL upregulates the expression of Breg markers by blood MZp from HIV-uninfected individuals, while this modulation is dampened by the addition of recombinant BAFF. Altogether, our observations suggest that strategies viewed to modulate levels of BAFF and/or APRIL could eventually represent a potential treatment target for CVD in PLHIV.

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Section: Discussionmentioning

confidence: 97%

Subclinical Atherosclerosis is Associated with Discrepancies in BAFF and APRIL Levels and Altered Breg Potential of Precursor-like Marginal Zone B-Cells in HIV Treated Individuals

Aranguren

Doyon-Laliberté

El‐Far

et al. 2022

Preprint

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“…The copyright holder for this preprint this version posted August 15, 2022. ; https://doi.org/10.1101/2022.08.15.504021 doi: bioRxiv preprint and CD73 expression levels in Tregs, despite ART [49]. In other chronic infections, such as hepatitis, a loss of CD73 and CD39 has also been observed and associated with viral load and high levels of inflammation [50].…”

Section: Discussionmentioning

confidence: 99%

“…Excess BAFF and Altered Breg Capacities in the context of HIV and CD73 expression levels in Tregs, despite ART [49]. In other chronic infections, such as hepatitis, a loss of CD73 and CD39 has also been observed and associated with viral load and high levels of inflammation [50].…”

Section: Discussionmentioning

confidence: 99%

“…Others have reported that the diminution of CD73 + B-cells and CD39 + CD73 + B-cells and diminution of ADO correlated with a loss of CD4 + T-cells and disease progression during HIV infection [47], [48]. Interestingly, the HIV context is also associated with downregulated CD39 and CD73 expression levels in Tregs, despite ART [49]. In other chronic infections, such as hepatitis, a loss of CD73 and CD39 has also been observed and associated with viral load and high levels of inflammation [50].…”

Section: Discussionmentioning

confidence: 99%

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Excess BAFF Alters NR4As Expression Levels and Breg Function of Human Precursor-like Marginal Zone B-cells in the Context of HIV-1 infection

Doyon-Laliberté

Aranguren

Byrns

et al. 2022

Preprint

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We have shown that excess B-cell activating factor (BAFF) in the blood of HIV-infected individuals, is concomitant with increased frequencies of precursor-like marginal zone (MZp) B-cells, early on and despite successful antiretroviral therapy (ART). We have recently reported that in HIV-uninfected individuals, MZp possess a strong B-cell regulatory (Breg) potential. As such, MZp B-cells highly express IL-10, the orphan nuclear receptors (NR)4A1, NR4A2, NR4A3, the regulatory molecule CD83, as well as ectonucleotidases CD39 and CD73, all of which are associated with regulation of inflammation. Moreover, the Breg function of MZp B-cells involves CD83 signals. Herein, in order to address the impact of HIV infection and excessive BAFF environment on MZp B-cells and their regulatory capacities, we have performed transcriptomic analyses by RNA-seq of sorted MZp B-cells from the blood of HIV-infected progressors. The Breg profile and function of blood MZp B-cells from HIV-infected progressors were assessed by flow-cytometry and light microscopy high content screening (HCS) analyses, respectively. In addition, the effects of excess BAFF on the Breg profile of MZp B-cells from HIV-uninfected controls were investigated in vitro. We report significant downregulation of NR4A1, NR4A2, NR4A3 and CD83 gene transcripts in blood MZp B-cells from HIV-infected progressors when compared to HIV-uninfected controls. NR4A1, NR4A3 and CD83 protein expression levels and Breg function were also downregulated in blood MZp B-cells from HIV-infected progressors and not restored by ART. Moreover, we observe decreased expression levels of NR4A1, NR4A3, CD83 and IL-10 by blood and tonsillar MZp B-cells from HIV-uninfected individuals following treatment with excess BAFF, which significantly diminished their regulatory function. These findings suggest that excess BAFF contributes to the alteration of the Breg potential of MZp B-cells, which could lead to a loss of immune surveillance, during HIV infection and possibly in other situations where BAFF is found in excess.

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“…Upregulation of CD39 + /CD73 + Tregs are thought to be protective against CVD and unstable plaque rupture [ 86–89 ]. Antiretroviral therapy-treated PWH with coronary artery disease have depressed levels of CD39 + /CD73 + Tregs, which may predispose them to atherosclerotic development [ 90 ]. How the adenosine pathway affects inflammasome activation in treated HIV will require additional studies to fully understand its role in HIV pathogenesis.…”

Section: Impact Of Adenosine Signaling On Inflammation and Comorbidities In Treated Human Immunodeficiency Virusmentioning

confidence: 99%

The Adenosine Pathway and Human Immunodeficiency Virus-Associated Inflammation

Hixson

Borker

Jackson

et al. 2021

Open Forum Infectious Diseases

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Human immunodeficiency virus (HIV) is associated with an increased risk of age-associated comorbidities and mortality compared to people without HIV. This has been attributed to HIV-associated chronic inflammation and immune activation despite viral suppression. The adenosine pathway is an established mechanism by which the body regulates persistent inflammation in order to limit tissue damage associated with inflammatory conditions. However, HIV infection is associated with derangements in the adenosine pathway that limits its ability to control HIV-associated inflammation. This article reviews the function of purinergic signaling and the role of the adenosine signaling pathway in HIV-associated chronic inflammation. This review also discusses the beneficial and potential detrimental effects of pharmacotherapeutic strategies targeting this pathway among people with HIV.

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Antiretroviral therapy-treated HIV-infected adults with coronary artery disease are characterized by a distinctive regulatory T-cell signature

Abstract: Supplemental Digital Content is available in the text

Cited by 11 publications

References 56 publications

Subclinical Atherosclerosis is Associated with Discrepancies in BAFF and APRIL Levels and Altered Breg Potential of Precursor-like Marginal Zone B-Cells in HIV Treated Individuals

Subclinical Atherosclerosis is Associated with Discrepancies in BAFF and APRIL Levels and Altered Breg Potential of Precursor-like Marginal Zone B-Cells in HIV Treated Individuals

Excess BAFF Alters NR4As Expression Levels and Breg Function of Human Precursor-like Marginal Zone B-cells in the Context of HIV-1 infection

The Adenosine Pathway and Human Immunodeficiency Virus-Associated Inflammation

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