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

Matheus Aranguren; Kim Doyon-Laliberté; Mohamed El-Far; Carl Chartrand-Lefebvre; Jean-Pierre Routy; Jean-Guy Barril; Benoît Trottier; Cécile Tremblay; Madeleine Durand; Johanne Poudrier; Michel Roger; Canadian HIV and Aging Cohort Study

doi:10.3390/vaccines11010081

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

Vaccines (Basel). 2022 Dec 30;11(1):81. doi: 10.3390/vaccines11010081.

Authors

Matheus Aranguren^{1

2}, Kim Doyon-Laliberté^{1

2}, Mohamed El-Far¹, Carl Chartrand-Lefebvre^{1

3}, Jean-Pierre Routy⁴, Jean-Guy Barril⁵, Benoît Trottier⁵, Cécile Tremblay^{1

2}, Madeleine Durand^{1

6}, Johanne Poudrier^{1

2}, Michel Roger^{1

2}; Canadian HIV and Aging Cohort Study

Affiliations

¹ Centre de Recherche du CHUM, Montréal, QC H2X 0A9, Canada.
² Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
³ Département de Radiologie, Radio-Oncologie et Médecine Nucléaire, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁴ Department of Medicine, McGill University Health Centre, McGill University, Montréal, QC H4A 3J1, Canada.
⁵ Clinique Médicale Urbaine du Quartier Latin, Montréal, QC H2L 4E9, Canada.
⁶ Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.

Abstract

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. The 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.

Keywords: APRIL; BAFF; Breg; HIV; MZp; aging; atherosclerosis; cardiovascular diseases.

Abstract

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