Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients

Bañó, M. Carmen; Morén, Constanza; Barroso, Sergio Espuelas; Juárez, Diana Luz; Guitart‐Mampel, Mariona; González‐Casacuberta, Ingrid; Cantó-Santos, Judith; Lozano, Ester; León, Agathe; Pedrol, Enric; Miró, Òscar; Tobías, Ester; Mallolas, Josép; Rojas, Jhon; Cardellach, Francesc; Martínez, Estebán; Garrabou, Glòria

doi:10.3389/fgene.2020.00497

Cited by 15 publications

(9 citation statements)

References 73 publications

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“…A recent study examining ART-related mitochondrial toxicity in HIV-exposed individuals prescribed a postexposure prophylaxis (PEP) regimen demonstrated mitochondrial toxicity after short-term ART use in the absence of HIV infection. Although PEP regimens using newer antiretrovirals, such as TDF plus FTC, showed less mtDNA depletion than regimens that included AZT ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

In VitroExposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression Profiles

Bowman

Cameron

Richardson

et al. 2020

Antimicrob Agents Chemother

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Background: The use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. Methods: Peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using RNAseq. Plasma lipids were measured using mass spectrometry. Results: PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888) genes had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass, and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. Conclusions: Exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function, and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.

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Section: Discussionmentioning

confidence: 99%

In VitroExposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression Profiles

Bowman

Cameron

Richardson

et al. 2020

Antimicrob Agents Chemother

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“…To determine mtDNA-CN in DNA, the mitochondrial 12S ribosomal RNA (mt12SrRNA) gene and the nuclear-encoded RNAse P gene were simultaneously determined in the same qPCR tube, as previously described ( 30 ) (as shown in the Supplementary Material ). The mtDNA-CN was calculated as the ratio 12SrRNA mtDNA copies/RNAseP DNA copies.…”

Section: Methodsmentioning

confidence: 99%

Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD

et al. 2021

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Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1 <50% ref.). In addition, we found that TL and mtDNA-CN were significantly correlated, but their relationship was positive in younger while negative in the older patients with COPD, suggesting a mitochondrial dysfunction. We conclude that TL, but not mtDNA-CN, is associated with the lung function impairment. Both young and old patients with severe COPD have evidence of accelerated ageing (shorter TL) but differ in the direction of the correlation between TL and mtDNA-CN in relation to age.

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“…ART-induced mitochondrial dysfunction may be explained, at least in part, by genetic or epigenetic modulations to mtDNA [ 74 ], which impair mitochondrial function and can increase oxidative stress. In particular, protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial damage [ 3 , 4 , 70 , 90 , 91 , 92 , 93 ]. Exposure to NRTIs has been shown to reduce levels of mtDNA and dysregulate the mitochondrial proteome via the inhibition of polymerase-γ [ 3 , 90 , 92 , 93 ].…”

Section: Pitfalls Of Art: Focus On the Cnsmentioning

confidence: 99%

“…In particular, protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial damage [ 3 , 4 , 70 , 90 , 91 , 92 , 93 ]. Exposure to NRTIs has been shown to reduce levels of mtDNA and dysregulate the mitochondrial proteome via the inhibition of polymerase-γ [ 3 , 90 , 92 , 93 ]. ART-treated mice exhibited modulated expression of mitochondrial transcription factor A (TFAM) [ 6 ].…”

Section: Pitfalls Of Art: Focus On the Cnsmentioning

confidence: 99%

Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity

Rudd

Toborek

2022

Biomolecules

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HIV can traverse the BBB using a Trojan horse-like mechanism. Hidden within infected immune cells, HIV can infiltrate the highly safeguarded CNS and propagate disease. Once integrated within the host genome, HIV becomes a stable provirus, which can remain dormant, evade detection by the immune system or antiretroviral therapy (ART), and result in rebound viraemia. As ART targets actively replicating HIV, has low BBB penetrance, and exposes patients to long-term toxicity, further investigation into novel therapeutic approaches is required. Viral proteins can be produced by latent HIV, which may play a synergistic role alongside ART in promoting neuroinflammatory pathophysiology. It is believed that the ability to specifically target these proviral reservoirs would be a vital driving force towards a cure for HIV infection. A novel drug design platform, using the in-tandem administration of several therapeutic approaches, can be used to precisely target the various components of HIV infection, ultimately leading to the eradication of active and latent HIV and a functional cure for HIV. The aim of this review is to explore the pitfalls of ART and potential novel therapeutic alternatives.

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Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients

Cited by 15 publications

References 73 publications

In VitroExposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression Profiles

In VitroExposure of Leukocytes to HIV Preexposure Prophylaxis Decreases Mitochondrial Function and Alters Gene Expression Profiles

Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD

Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity

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