Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion

Proust, Alizé; Barat, Corinne; Lebœuf, Mathieu; Drouin, Jean; Tremblay, Michel J.

doi:10.1186/s12974-017-1019-y

Cited by 18 publications

(29 citation statements)

References 64 publications

(68 reference statements)

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“…We have previously demonstrated that the LRA bryostatin-1 and JQ1 profoundly affect the physiology of human astrocytes (Proust et al, 2017). It was thus legitimate to assess whether treatment with bryostatin-1 and/or JQ1 can compromise the capacity of astrocytes to clear Aβ.…”

Section: Discussionmentioning

confidence: 99%

“…They also induce oxidative stress in astrocytes, by binding to RAGE which induces ROS production via NOX complex activation (Askarova, Yang, Sheng, Sun, & Lee, 2011). Conversely, phagocytosis without degradation might provoke an intracellular accumulation that could cause inflammation, adding fuel to the inflammatory environment already established by HIV-1 and possibly enhanced by some LRA treatments (Proust et al, 2017). In addition, it has been shown that accumulation of Aβ protofibrils induces severe lysosome failure in the phagocytic astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Infected cells were then left untreated for 7 days before being used in our experiments to ensure that initial cell responses to acute infection and/or exposure to the VSV-G glycoproteins are completed, and to more adequately mimic the chronic infection seen in vivo. Our experiments were performed with two LRA, bryostatin-1 and JQ1 (used either alone or in combination), which are expected to cross the BBB (Churchill, Cowley, Wesselingh, Gorry, & Gray, 2015) and that were shown in our previous work to profoundly affect the physiology of human astrocytes (Proust et al, 2017). These two LRA were used at non-toxic concentrations proved to be effective at reversing HIV-1 latency (Dental et al, 2017;Mehla et al, 2010) and cells were treated for a period of time routinely used in reactivation studies (i.e., 24 hr) (Darcis et al, 2015;Gray et al, 2016).…”

Section: Uptake Of Aβ Monomers and Protofibrils By Astrocytes Is Momentioning

confidence: 99%

“…These two LRA were used at non-toxic concentrations proved to be effective at reversing HIV-1 latency (Dental et al, 2017;Mehla et al, 2010) and cells were treated for a period of time routinely used in reactivation studies (i.e., 24 hr) (Darcis et al, 2015;Gray et al, 2016). Importantly, this treatment time period is sufficient to induce physiological effects in astrocytes (Proust et al, 2017).…”

Section: Uptake Of Aβ Monomers and Protofibrils By Astrocytes Is Momentioning

confidence: 99%

“…Moreover, bryostatin-1 enhances transmigration of neutrophils across an in vitro blood-brain barrier model and induces formation of neutrophil extracellular traps. In contrast, the bromodomain inhibitor JQ1 could dampen some of the proinflammatory activities of bryostatin-1 (Proust, Barat, Leboeuf, Drouin, & Tremblay, 2017).…”

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confidence: 96%

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HIV‐1 infection and latency‐reversing agents bryostatin‐1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes

Proust

Barat

Lebœuf

et al. 2020

Glia

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Since the introduction of the combined antiretroviral therapy, HIV‐1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general population. Nevertheless, various age‐related pathologies such as neurocognitive disorders have emerged as serious complications. A “shock and kill” strategy using latency‐reversing agents (LRA) to reactivate HIV‐1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV‐1‐infected brains, we investigated the consequences of HIV‐1 infection and treatment with two LRA (bryostatin‐1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV‐1‐infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin‐1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ‐loaded microvesicles. Thus, both HIV‐1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV‐1‐infected persons.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Uptake Of Aβ Monomers and Protofibrils By Astrocytes Is Momentioning

confidence: 99%

Section: Uptake Of Aβ Monomers and Protofibrils By Astrocytes Is Momentioning

confidence: 99%

mentioning

confidence: 96%

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HIV‐1 infection and latency‐reversing agents bryostatin‐1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes

Proust

Barat

Lebœuf

et al. 2020

Glia

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Impact of latency‐reversing agents on human macrophage physiology

Hany

Turmel

Barat

et al. 2022

Immunity Inflam & Disease

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Introduction HIV‐1 eradication is hindered by the presence of inducible long‐lived reservoirs of latently infected cells which rapidly disseminate viral particles upon treatment interruption. Eliminating these reservoirs by the so‐called shock and kill strategy represents a crucial concept toward an HIV‐1 cure. Several molecules called latency‐reversing agents (LRAs) are under intensive investigations to reactivate virus gene expression. These studies are mainly conducted on CD4 + T cells where LRAs are well tolerated and did not induce global cellular activation. However, despite their broad spectrum, the putative impact of LRAs on other cellular reservoirs such as macrophages is still ill‐defined. Methods We investigated the impact of the protein kinase C (PKC) activator bryostatin‐1, bromodomain inhibitor JQ1 and histone deacetylase inhibitor romidepsin used either alone or in combination on human primary monocyte‐derived macrophages (MDMs). Results We demonstrate that bryostatin‐1, JQ1, and romidepsin or their combinations are not toxic at nanomolar concentrations but induce metabolic and morphologic alterations of MDMs. Bryostatin‐1 triggered the secretion of pro‐inflammatory cytokines, while JQ‐1 decreased it. Phagocytosis and endocytosis were modestly impaired upon bryostatin‐1 treatment whereas efferocytosis was markedly downregulated by romidepsin. Despite its pro‐inflammatory profile, bryostatin‐1 did not induce classically activated macrophage markers. Finally, we reveal that conditioned medium from bryostatin‐1‐treated macrophages did not potentiate its reactivation feature. Conclusions Our study reveals that LRAs can diversely impact basic physiologic features of human primary macrophages and could potentially decrease reactivation of nearby CD4 + T cells latently infected with HIV‐1. Our observations further stress the need to include different cell populations when assessing HIV‐1 cure strategies.

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Shock and kill within the CNS: A promising HIV eradication approach?

Nühn

Gumbs

Buchholtz

et al. 2022

Journal of Leukocyte Biology

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The most studied HIV eradication approach is the “shock and kill” strategy, which aims to reactivate the latent reservoir by latency reversing agents (LRAs) and allowing elimination of these cells by immune‐mediated clearance or viral cytopathic effects. The CNS is an anatomic compartment in which (persistent) HIV plays an important role in HIV‐associated neurocognitive disorder. Restriction of the CNS by the blood–brain barrier is important for maintenance of homeostasis of the CNS microenvironment, which includes CNS‐specific cell types, expression of transcription factors, and altered immune surveillance. Within the CNS predominantly myeloid cells such as microglia and perivascular macrophages are thought to be a reservoir of persistent HIV infection. Nevertheless, infection of T cells and astrocytes might also impact HIV infection in the CNS. Genetic adaptation to this microenvironment results in genetically distinct, compartmentalized viral populations with differences in transcription profiles. Because of these differences in transcription profiles, LRAs might have different effects within the CNS as compared with the periphery. Moreover, reactivation of HIV in the brain and elimination of cells within the CNS might be complex and could have detrimental consequences. Finally, independent of activity on latent HIV, LRAs themselves can have adverse neurologic effects. We provide an extensive overview of the current knowledge on compartmentalized (persistent) HIV infection in the CNS and on the “shock and kill” strategy. Subsequently, we reflect on the impact and promise of the “shock and kill” strategy on the elimination of persistent HIV in the CNS.

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Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion

Cited by 18 publications

References 64 publications

HIV‐1 infection and latency‐reversing agents bryostatin‐1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes

HIV‐1 infection and latency‐reversing agents bryostatin‐1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes

Impact of latency‐reversing agents on human macrophage physiology

Shock and kill within the CNS: A promising HIV eradication approach?

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