title: HIV-1 Latency-Reversing Agents Prostratin and Bryostatin-1 Induce Blood-Brain Barrier Disruption/Inflammation and Modulate Leukocyte Adhesion/Transmigration.
abstract: 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.
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and.
authors.forename: Clélia
authors.initials: C
authors.lastname: Dental
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and.
authors.forename: Alizé
authors.identifier: 0000-0003-2809-2835
authors.initials: A
authors.lastname: Proust
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and.
authors.forename: Michel
authors.identifier: 0000-0002-2353-7535
authors.initials: M
authors.lastname: Ouellet
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and.
authors.forename: Corinne
authors.initials: C
authors.lastname: Barat
authors.affiliation: Axe des Maladies Infectieuses et Immunitaires, Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec G1V 4G2, Canada; and michel.j.tremblay@crchudequebec.ulaval.ca.|Département de Microbiologie-Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Quebec City, Quebec G1V 0A6, Canada.
authors.forename: Michel J
authors.identifier: 0000-0002-6919-7847
authors.initials: MJ
authors.lastname: Tremblay
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D054713:Bryostatins / Q000009:adverse effects / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D000077209:Decitabine; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D010703:Phorbol Esters / Q000009:adverse effects / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000032:analysis; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D000081:Acetamides; D001381:Azepines; C518299:BIX 01294; D054713:Bryostatins; C111835:CCL2 protein, human; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D016207:Cytokines; C407243:F11R protein, human; D010703:Phorbol Esters; D011799:Quinazolines; D011956:Receptors, Cell Surface; D018799:Intercellular Adhesion Molecule-1; C046785:bryostatin 1; C070999:prostratin; D000077209:Decitabine; C014026:hexamethylene bisacetamide; D001374:Azacitidine