Antiretroviral Drugs Impact Autophagy with Toxic Outcomes

Cheney, Laura; Barbaro, John M.; Berman, Joan W.

doi:10.3390/cells10040909

Cited by 20 publications

(18 citation statements)

References 80 publications

(166 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Over 38 million people with HIV (PWH) are living worldwide [ 1 ]. HIV is treated with antiretroviral therapy (ART), which suppresses viral replication in infected cells but does not eradicate infection [ 2 ]. The ongoing presence of HIV in tissue reservoirs causes PWH to experience long-term comorbidities for which the underlying mechanisms are not extensively characterized [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis

2022

Self Cite

View full text Add to dashboard Cite

HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity. Macroautophagy is a vital intracellular pathway that can regulate, in part, these deleterious processes. We found in HIV-infected primary human macrophages that meth inhibits phagocytosis of aggregated amyloid-β, increases total ROS, and dysregulates autophagic processes. Treatment with widely prescribed ART drugs had minimal effects, although there may be an improvement in phagocytosis when co-administered with meth. Pharmacologically inhibited lysosomal degradation, but not induction of autophagy, further increased ROS in response to meth. Using mass spectrometry, we identified the differentially expressed proteins in meth-treated, HIV-infected macrophages that participate in phagocytosis, mitochondrial function, redox metabolism, and autophagy. Significantly altered proteins may be novel targets for interventional strategies that restore functional homeostasis in HIV-infected macrophages to improve neurocognition in people with HIV-NCI using meth.

show abstract

Section: Introductionmentioning

confidence: 99%

Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis

2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…ART alone also increased phagocytosis in both uninfected and HIV‐infected MDMs (Figure 1). We tested a combination of tenofovir, emtricitabine, and raltegravir because it represents a commonly prescribed regimen to treat HIV infection 9 . The off‐target effects in MDMs of these 3 drugs outside the context of HIV replication are not extensively characterized and may contribute to comorbidities associated with long‐term HIV infection.…”

Section: Discussionmentioning

confidence: 99%

“…The off‐target effects in MDMs of these 3 drugs outside the context of HIV replication are not extensively characterized and may contribute to comorbidities associated with long‐term HIV infection. Tenofovir and emtricitabine can inhibit DNA polymerase Ɣ, which helps replicate mitochondrial DNA 9 . This may cause downstream changes in metabolism that modify activation.…”

Section: Discussionmentioning

confidence: 99%

“…The annual HIV Surveillance Report from the Center for Disease Control published in 2020 indicated that nearly 4000 injection drug users were newly diagnosed with HIV 8 . These people must take ART for the rest of their lives to maintain peripheral and CNS viral suppression 9 . It has been documented since the mid‐2000s that opioid use reduces neurocognitive abilities in both PWH and in uninfected individuals 10,11 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Morphine disrupts macrophage functions even during HIV infection

Barbaro

Jaureguiberry‐Bravo

Berman

2022

Journal of Leukocyte Biology

View full text Add to dashboard Cite

HIV‐associated neurocognitive impairment (HIV‐NCI) is a debilitating comorbidity that reduces quality of life in 15–40% of people with HIV (PWH) taking antiretroviral therapy (ART). Opioid use has been shown to increase neurocognitive deficits in PWH. Monocyte‐derived macrophages (MDMs) harbor HIV in the CNS even in PWH on ART. We hypothesized that morphine (MOR), a metabolite of heroin, further dysregulates functional processes in MDMs to increase neuropathogenesis. We found that, in uninfected and HIV‐infected primary human MDMs, MOR activates these cells by increasing phagocytosis and up‐regulating reactive oxygen species. Effects of MOR on phagocytosis were dependent on μ‐opioid receptor activity and were mediated, in part, by inhibited lysosomal degradation of phagocytized substrates. All results persisted when cells were treated with both MOR and a commonly prescribed ART cocktail, suggesting minimal impact of ART during opioid exposure. We then performed mass spectrometry in HIV‐infected MDMs treated with or without MOR to determine proteomic changes that suggest additional mechanisms by which opioids affect macrophage homeostasis. Using downstream pathway analyses, we found that MOR dysregulates ER quality control and extracellular matrix invasion. Our data indicate that MOR enhances inflammatory functions and impacts additional cellular processes in HIV‐infected MDMs to potentially increases neuropathogenesis in PWH using opioids.

show abstract

“…The most well-studied type is macroautophagy, hereby termed autophagy, which can degrade cargo “in bulk” or selectively target specific cellular components for degradation [ 29 ]. In autophagy, a double-membraned organelle, the autophagosome (APG), forms and encloses around cytosolic cargo to be degraded [ 30 ]. During this process, Microtubule-associated Protein 1A/1B-Light Chain 3 (LC3) gets lipidated, forming LC3II, and associates with the inner and outer membrane of the forming APG, serving as a marker to monitor autophagic activity [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

HIV Increases the Inhibitory Impact of Morphine and Antiretrovirals on Autophagy in Primary Human Macrophages: Contributions to Neuropathogenesis

Barbaro

Cuervo

Berman

2021

Cells

Self Cite

View full text Add to dashboard Cite

HIV enters the CNS early after peripheral infection, establishing reservoirs in perivascular macrophages that contribute to development of HIV-associated neurocognitive disorders (HAND) in 15–40% of people with HIV (PWH) despite effective antiretroviral therapy (ART). Opioid use may contribute to dysregulated macrophage functions resulting in more severe neurocognitive symptoms in PWH taking opioids. Macroautophagy helps maintain quality control in long-lived cell types, such as macrophages, and has been shown to regulate, in part, some macrophage functions in the CNS that contribute to HAND. Using Western blotting and confocal immunofluorescence in primary human macrophages, we demonstrated that morphine and a commonly prescribed ART regimen induce bulk autophagy. Morphine and ART also inhibited completion of autophagy. HIV infection increased these inhibitory effects. We also examined two types of selective autophagy that degrade aggregated proteins (aggrephagy) and dysfunctional mitochondria (mitophagy). Morphine and ART inhibited selective autophagy mediated by p62 regardless of HIV infection, and morphine inhibited mitophagic flux in HIV-infected cells demonstrating potential mitotoxicity. These results indicate that inhibition of autophagy, both in bulk and selective, in CNS macrophages may mediate neurocognitive dysfunction in PWH using opioids. Increasing autophagic activity in the context of HIV may represent a novel therapeutic strategy for reducing HAND in these individuals.

show abstract

Antiretroviral Drugs Impact Autophagy with Toxic Outcomes

Cited by 20 publications

References 80 publications

Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis

Methamphetamine Dysregulates Macrophage Functions and Autophagy to Mediate HIV Neuropathogenesis

Morphine disrupts macrophage functions even during HIV infection

HIV Increases the Inhibitory Impact of Morphine and Antiretrovirals on Autophagy in Primary Human Macrophages: Contributions to Neuropathogenesis

Contact Info

Product

Resources

About