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. 2024 Mar 14;229(3):763-774.
doi: 10.1093/infdis/jiad503.

Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia

Mehdi Benlarbi  1   2 , Jonathan Richard  1   2 , Catherine Bourassa  1 , William D Tolbert  3 , Carl Chartrand-Lefebvre  4 , Gabrielle Gendron-Lepage  1 , Mohamed Sylla  1 , Mohamed El-Far  1 , Marc Messier-Peet  1 , Camille Guertin  1   2 , Isabelle Turcotte  1   2 , Rémi Fromentin  1   2 , Myriam Maude Verly  1 , Jérémie Prévost  1   2 , Andrew Clark  5 , Walther Mothes  6 , Daniel E Kaufmann  1   7 , Frank Maldarelli  8 , Nicolas Chomont  1   2 , Philippe Bégin  9   10 , Cécile Tremblay  1   2 , Jean-Guy Baril  11   12 , Benoit Trottier  11   12 , Sylvie Trottier  13 , Ralf Duerr  14   15   16 , Marzena Pazgier  3 , Madeleine Durand  1   10 , Andrés Finzi  1   2
Affiliations

Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia

Mehdi Benlarbi et al. J Infect Dis. .

Abstract

Background: Chronic inflammation persists in some people living with human immunodeficiency virus (HIV) during antiretroviral therapy and is associated with premature aging. The glycoprotein 120 (gp120) subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasma soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and subclinical cardiovascular disease in participants of the Canadian HIV and Aging Cohort Study with undetectable viremia.

Methods: Cross-sectional assessment of sgp120 and anti-cluster A antibodies was performed in 386 individuals from the cohort. Their association with proinflammatory cytokines and subclinical coronary artery disease was assessed using linear regression models.

Results: High levels of sgp120 and anti-cluster A antibodies were inversely correlated with CD4+ T cell count and CD4/CD8 ratio. The presence of sgp120 was associated with increased levels of interleukin 6. In participants with detectable atherosclerotic plaque and detectable sgp120, anti-cluster A antibodies and their combination with sgp120 levels correlated positively with the total volume of atherosclerotic plaques.

Conclusions: This study showed that sgp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of people living with HIV, contributing to the development of premature comorbid conditions.

Keywords: HIV-1; anti–cluster A antibodies; cardiovascular diseases; chronic inflammation; soluble gp120.

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Conflict of interest statement

Potential conflicts of interest. W. M., C. T., M. P., and A. F. received funding from ViiV Healthcare. A. C. is a full-time employee of ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Detection of soluble glycoprotein 120 (sgp120) in people living with human immunodeficiency virus (HIV) with undetectable viremia is associated with inflammation. Representative stratification is shown for 157 people living with HIV, based on levels of sgp120 (A) and interleukin 6 (IL-6) (B). Statistical analysis was performed using Mann-Whitney U tests. *P < .05 ; **P < .01 ; ***P < .001 . Abbreviations: HIV−, HIV negative; HIV+, HIV positive; NS, not significant; RU, relative units.
Figure 2.
Figure 2.
Anti–cluster A antibodies are inversely correlated with CD4+ T-cell counts in people living with human immunodeficiency virus (PLWH) presenting with high levels of soluble glycoprotein 120 (sgp120). Correlations between CD4+ T-cell counts and anti–cluster A antibody levels are shown for 386 PLWH, stratified by sgp120 levels. Correlations are shown for the total study population (A) and for PLWH with undetectable sgp120 (B), low levels of sgp120 (sgp120low) (C), or high levels of sgp120 (sgp120high) (D). Levels of anti–cluster A antibodies were log2 transformed. Univariable and multivariable linear regressions were performed, with the beta parameters representing the mean predicted change in absolute CD4+ cell counts for each 1-log2 increase in titers of anti–cluster A antibodies. Multivariable models are adjusted for age, sex, ethnicity, smoking status, duration of antiretroviral therapy, nadir CD4+ cell counts, and levels of anti–CD4 binding site antibodies. Abbreviations: CI, confidence interval; RU, relative units.
Figure 3.
Figure 3.
Soluble glycoprotein 120 (sgp120) acts as an “effect modifier” of the associations between clinical and laboratory markers. Its presence modifies the network of associations between clinical and laboratory parameters in people living with human immunodeficiency virus (HIV) with undetectable viremia on stratification by undetectable sgp120 (A), low levels of sgp120 (sgp120low) (B), or high levels of sgp120 (sgp120high) (C). Spearman rank correlations were computed and graphed as edge bundling correlation plots, using program R v. 4.1.2. Statistical tests were 2 sided, and differences were considered significant at P < .05. Edges are only shown if P < .05, and nodes are sized according to the connecting edges’ r values. Nodes are color coded according to the grouping of variables. Abbreviations: Abs, antibodies; ART, antiretroviral-therapy; BDNF, brain-derived neurotrophic factor; Chol, cholesterol; Fram score, Framingham risk score; HDL, high-density lipoproteins; IL-1β, interleukin 1β; LDL, low-density lipoproteins; sCD14, soluble CD14; sCD163, soluble CD163; TNF, tumor necrosis factor; TPV, total atherosclerotic plaque volume; TSLP, thymic stromal lymphopoietin.
Figure 4.
Figure 4.
The combination of soluble glycoprotein 120 (sgp120) levels and anti–cluster A antibodies correlates positively with subclinical cardiovascular disease. Associations are displayed between the size of coronary artery plaque volume and sgp120 levels (A), anti–cluster A antibodies (B), and the multiplicative combination of both (C) in people living with human immunodeficiency virus who are positive for sgp120 and have detectable subclinical cardiovascular disease. Values for sgp120, anti–cluster A antibodies, and total plaque volume (mm3) were log2 transformed. Univariable and multivariable linear regressions were performed, with the beta parameters representing the mean predicted change in log total plaque volume for each 1-log2 increase in the exposure. Multivariable models are adjusted for age, sex, smoking status, low- or high-density lipoproteins, diabetes mellitus, hypertension, alcohol use disorder, intravenous drug use, and duration of antiretroviral therapy. Abbreviations: CI, confidence interval; RU, relative units.
Figure 5.
Figure 5.
Longitudinal analysis of soluble glycoprotein 120 (sgp120) and some inflammatory markers. Levels of sgp120 (A), interleukin 6 (IL-6) (B), tumor necrosis factor (TNF) α (C), and soluble CD163 (sCD163) (D) were measured over time for 9 participants with detectable levels of sgp120. Dashed line in A represents seropositivity threshold established in plasma samples from uninfected participants. Abbreviation: RU, relative units.
Figure 6.
Figure 6.
Longitudinal analysis of anti­­–cluster A antibodies and CD4+ T-cell counts. Levels of anti–cluster A antibodies (A) and CD4+ T-cell counts (B) were measured over time for 9 participants with detectable levels of soluble glycoprotein 120 (sgp120). Abbreviation: RU, relative units.
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