HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration.
Clélia DentalAlizé ProustMichel OuelletCorinne BaratMichel J TremblayPublished in: Journal of immunology (Baltimore, Md. : 1950) (2016)
A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4+ and CD8+ T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB.
Keyphrases
- blood brain barrier
- hiv infected
- antiretroviral therapy
- endothelial cells
- oxidative stress
- human immunodeficiency virus
- hiv positive
- cerebral ischemia
- hiv infected patients
- hiv aids
- induced apoptosis
- peripheral blood
- human health
- poor prognosis
- transcription factor
- sars cov
- induced pluripotent stem cells
- pluripotent stem cells
- subarachnoid hemorrhage
- signaling pathway
- candida albicans
- cell cycle arrest
- cell migration
- pseudomonas aeruginosa
- south africa
- cell proliferation
- men who have sex with men
- pi k akt
- cell adhesion
- endoplasmic reticulum stress
- brain injury
- immune response
- cerebral blood flow