HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study

Sophie Perrin, Jonathan Cremer, Patrice Roll, Olivia Faucher, Amélie Ménard, Jacques Reynes, Pierre Dellamonica, Alissa Naqvi, Joëlle Micallef, Elisabeth Jouve, Catherine Tamalet, Caroline Solas, Christel Pissier, Isabelle Arnoux, Corine Nicolino-Brunet, Léon Espinosa, Nicolas Lévy, Elise Kaspi, Andrée Robaglia-Schlupp, Isabelle Poizot-Martin, Pierre Cau, Sophie Perrin, Jonathan Cremer, Patrice Roll, Olivia Faucher, Amélie Ménard, Jacques Reynes, Pierre Dellamonica, Alissa Naqvi, Joëlle Micallef, Elisabeth Jouve, Catherine Tamalet, Caroline Solas, Christel Pissier, Isabelle Arnoux, Corine Nicolino-Brunet, Léon Espinosa, Nicolas Lévy, Elise Kaspi, Andrée Robaglia-Schlupp, Isabelle Poizot-Martin, Pierre Cau

Abstract

Background: The ANRS EP45 "Aging" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence.

Methods: 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; https://ichgcp.net/clinical-trials-registry/NCT01038999" title="See in ClinicalTrials.gov">NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm(3). ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting.

Results: Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria.

Conclusions: In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.

Conflict of interest statement

Competing Interests: GlaxoSmithKline and Boehringen Mannheim grants were received. This does not alter the authors’ adherence to all PLoS ONE policies on sharing data and materials. The funding was not related to employment, consultancy, patents and product in development or marketed products.

Figures

Figure 1. Flow cytometric analysis of ROS…
Figure 1. Flow cytometric analysis of ROS production revealed two subpopulations of both CD14+ monocytes and lymphocytes.
(A to C) Monocytes. (A) CD14+/SSC monocyte gating. (B) Representative zebra plot based on side scatter and ROS production showing low- and high-ROS producing cell subpopulations. (C) Histogram illustrating ROS production as a function of cell count (low-ROS production, gray; high-ROS production, red). ROS production levels (MFI ± SD) are indicated as percentages relative to CD14+ monocytes. The percentages of high-ROS monocytes were not statistically different between the groups: Control: 75.8±21.7%; ART naive: 70.7±19.4%; 2NRTI+1PI/r: 71.1±21.1%; 2NRTI+1NNRTI: 71.0±22.8%; 3NRTI: 66.2±23.7%. (D to F) Lymphocytes. (D) FSC/SSC lymphocyte gating. (E) Representative zebra plot based on side scatter and ROS production showing low- and high-ROS producing cell subpopulations. (F) Histogram illustrating ROS production as a function of cell count (low-ROS production, gray; high-ROS production, red). ROS production levels (MFI ± SD) are indicated as percentages relative to FSC/SSC-selected lymphocytes. The percentages of high-ROS lymphocytes were not statistically different between the groups: Control: 55.4±12.7%; ART naive: 48.0±14.1%; 2NRTI+1PI/r: 55.1±13.8%; 2NRTI+1NNRTI: 50.1±14.1%; 3NRTI: 47.6±15.0%. ROS production by the low- and high-ROS subpopulations was statistically different in both HIV and ART patients.
Figure 2. Determination of mitochondrial inner membrane…
Figure 2. Determination of mitochondrial inner membrane potential (ΔΨm) in lymphocytes and monocytes.
JC-1 is a cationic carbocyanine probe that exibits a potential-dependent accumulation in mitochondria as either a monomer at low concentrations (green fluorescence) or as aggregates at higher concentrations (red fluorescence) . Therefore, the red/green fluorescence intensity ratio illustrates ΔΨm. (A to C) Monocytes. (A) CD14+/SSC monocyte gating. (B) Representative zebra plot based on side scatter and ΔΨm. (C) Representative zebra plot based on side scatter and ΔΨm after inhibition of ΔΨm with CCCP (control experiment). (D to F) Lymphocytes. (D) FSC/SSC lymphocyte gating. (E) Representative zebra plot based on side scatter and ΔΨm. Two lymphocyte subpopulations were distinguished (low-ΔΨm, bottom right quadrants; high-ΔΨm, top right quadrants). The top and bottom right quadrants indicate the ΔΨm mean values (cell percentages). The percentages of low-ΔΨm lymphocytes were: Control: 14.7±8.2%; ART naive: 12.56±4.4% (statistically different from control); 2NRTI+1PI/r: 17.0±8.4%; 2NRTI+1NNRTI: 15.3±7.3%; 3NRTI: 16.3±5.1%. (F) Representative zebra plot based on side scatter and ΔΨm after inhibition of ΔΨm with CCCP (control experiment).
Figure 3. Mitochondrial functional parameters: differential effects…
Figure 3. Mitochondrial functional parameters: differential effects of HIV-1 infection and ART on lymphocytes and monocytes.
(A, E) Discriminant analysis using ROS and ΔΨm parameters. The five cohort populations are delineated by their 95% confidence circles around the means. The perpendicular axes describe the combined variance of the parameters analysed (lymphocytes: 77.26%, monocytes: 92.25%). The contributions of each parameter to the variances on the X and Y axes are shown in the insets. (A) Lymphocytes. ART naive patients are statistically different to control subjects. ART partially rescues mitochondrial parameter changes induced by HIV infection. Inset: The 8 mitochondrial parameters used were: a: Basal ROS production by high-ROS lymphocytes (see Figure 3B). b: PMA/Basal ratio of ROS production by high-ROS lymphocytes (see Figure 3C). cHigh: ΔΨm of high-ΔΨm lymphocytes. cLow: ΔΨm of low-ΔΨm lymphocytes (see Figure 3D). cLow%: Percentage of low-ΔΨm lymphocytes. dHigh: Basal to CCCP ΔΨm ratio of high-ΔΨm lymphocytes. dLow: Basal to CCCP ΔΨm ratio of low-ΔΨm lymphocytes. dLow%: CCCP to Basal ratio of low-ΔΨm lymphocyte percentage. (E) Monocytes. ART naive patients are close to control subjects whereas ART combinations are more dispersed. Inset: The 4 mitochondrial parameters used were: a: Basal ROS production by high-ROS monocytes (see Figure 3F). b: PMA to Basal ratio of ROS production by high-ROS monocytes (see Figure 3G). c: ΔΨm of monocytes (see Figure 3H). d: Basal to CCCP ΔΨm ratio of monocytes. (B to D; F to H) Box plots (XLSTAT) displaying 1st quartile (Q1), median, mean (displayed by ‘+’), 3rd quartile (Q3) together with both lower and upper limits were calculated as follows: lower limit = Xi such that {Xi – [Q1–1.5 (Q3– Q1)]} is the minimum and Xi ≥ Q1–1.5 (Q3– Q1); upper limit = Yi such that { Yi – [Q3+1.5 (Q3– Q1)]} is the minimum and Yi ≤ Q3+1.5 (Q3– Q1). *p<0,05, **p<0,01.
Figure 4. Correlation between mitochondrial functional parameters…
Figure 4. Correlation between mitochondrial functional parameters and viral load in cells from ART naive patients.
(A) ROS production by high-ROS lymphocytes (r = 0.355, p = 0.029, n = 38). (B) ΔΨm of high-ΔΨm lymphocytes (r = −0.417, p = 0.007, n = 40). (C) Percentage of low-ΔΨm lymphocytes (r = 0.457, p = 0.003, n = 40). (D) ROS production by high-ROS monocytes (r = 0.164, p = 0.288, n = 44) (E) ΔΨm of monocytes (r = −0.455, p = 0.003, n = 40).
Figure 5. Mitochondrial morphological parameters: differential effects…
Figure 5. Mitochondrial morphological parameters: differential effects of HIV-1 infection and ART on lymphocytes and monocytes.
(A, E) Discriminant analysis using three mitochondrial morphological parameters. The five cohort populations are delineated by their 95% confidence circles around the means. The two perpendicular axes describe the combined variance of the parameters analysed (lymphocytes: 90.66%, monocytes: 98.73%). The contributions of each parameter to the variances on the X and Y axes are shown in the insets. Inset: The 3 mitochondrial parameters used were: Vv%: Volume density (lymphocytes: see Figure 5B; monocytes: see Figure 5F). Frag: Fragmentation (lymphocytes: see Figure 5C; monocytes: see Figure 5G). Bran: Branching (lymphocytes: see Figure 5D; monocytes: see Figure 5H). (A) Lymphocytes ART naive patients and control subjects are statistically different. Mitochondrial changes induced by HIV infection are partially reduced by ART. (E) Monocytes ART naive patients exhibit no variations compared to control subjects, while significant differences are observed for the three ART groups. (B to D; F to H) Box plots: *p<0,05, **p<0,01.

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