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The journal of immunology : official journal of the American Association of Immunologists v.198 no.3, 2017년, pp.1229 - 1241   SCI SCIE
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HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood–Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration

Dental, Clélia (Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec–Université ) ; Proust, Alizé (Laval, Quebec City, Quebec G1V 4G2, Canada ) ; Ouellet, Michel (and ) ; Barat, Corinne (Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec–Université ) ; Tremblay, Michel J. (Laval, Quebec City, Quebec G1V 4G2, Canada ) ;
  • 초록  

    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.


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