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Effect of HIV infection and antiretroviral therapy on immune cellular functions
Marek Korencak, … , Brian K. Agan, Hendrik Streeck
Marek Korencak, … , Brian K. Agan, Hendrik Streeck
Published June 20, 2019
Citation Information: JCI Insight. 2019;4(12):e126675. https://doi.org/10.1172/jci.insight.126675.
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Research Article AIDS/HIV Immunology

Effect of HIV infection and antiretroviral therapy on immune cellular functions

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Abstract

During chronic HIV infection, immune cells become increasingly dysfunctional and exhausted. Little is known about how immune functions are restored after initiation of antiretroviral therapy (ART). In this study, we assessed cellular and metabolic activity and evaluated the effect of individual antiretrovirals on cellular subsets ex vivo in ART-treated and treatment-naive chronically HIV-infected individuals. We observed that cellular respiration was significantly decreased in most immune cells in chronic HIV infection. The respiration was correlated to immune activation and the inhibitory receptor programmed cell death 1 on CD8+ T cells. ART restored the metabolic phenotype, but the respiratory impairment persisted in CD4+ T cells. This was particularly the case for individuals receiving integrase strand transfer inhibitors. CD4+ T cells from these individuals showed a significant reduction in ex vivo proliferative capacity compared with individuals treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. We noticed a significant decrease in respiration of cells treated with dolutegravir (DLG) or elvitegravir (EVG) and a switch from polyfunctional to TNF-α–dominated “stress” immune response. There was no effect on glycolysis, consistent with impaired mitochondrial function. We detected increased levels of mitochondrial ROS and mitochondrial mass. These findings indicate that EVG and DLG use is associated with slow proliferation and impaired respiration with underlying mitochondrial dysfunction, resulting in overall decreased cellular function in CD4+ T cells.

Authors

Marek Korencak, Morgan Byrne, Enrico Richter, Bruce T. Schultz, Patrick Juszczak, Julie A. Ake, Anuradha Ganesan, Jason F. Okulicz, Merlin L. Robb, Buena de los Reyes, Sandra Winning, Joachim Fandrey, Timothy H. Burgess, Stefan Esser, Nelson L. Michael, Brian K. Agan, Hendrik Streeck

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Figure 3

Assessment of effect of ARTs on CD4+ T cell metabolism and functionality (n = 8).

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Assessment of effect of ARTs on CD4+ T cell metabolism and functionality...
Basal (A) and maximal respiration (B) of CD4+ T cells exposed to different ARTs for 3 days. Significant reduction in OCR was observed for CD4+ T cells treated with DLG and EVG. FTC, emtricitabine; AZT, zidovudine; 3TC, lamivudine; RLP, rilpivirine; DRV, darunavir ethanolate; RTV, ritonavir; R, Ruskinn Invivo Hypoxia Workstation; HOX, hypoxic condition. (C) HIF-1α protein expression and Glut1 and PGK1 mRNA levels of cells treated with DMSO, NRTIs (represented by FTC), NNRTIs (represented by RLP), ISNTIs (represented by DLG), and PIs (represented by DRV) showing no significant differences. (D) Membrane potential without and with mitochondrial uncoupler FCCP. (E) Assessment of CD4+ T cell polyfunctionality after stimulation with SEB in the presence of different ARTs. Overall reduced functionality was observed in the presence of DLG and EVG for CD107a, IFN-γ, IL-2, macrophage inflammatory protein-1β (MIP-1β), and TNF-α. (F) SPICE analysis showing a shift in the polyfunctionality profile of CD4+ T cells stimulated in the presence of DLG and EVG toward a TNF-α–dominated, monofunctional response. Plots show individual values with the mean ± SD. Box plots show the median value within fifth to 95th percentile. Statistical significance was assessed by RM 1-way ANOVA test with Holm-Šídák’s multiple-comparisons test (*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001).

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