Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells

• Published in: Journal of neurovirology 2016-08, Vol.22 (4), p.455-463
• Main Authors: Gray, Lachlan R., On, Hung, Roberts, Emma, Lu, Hao K., Moso, Michael A., Raison, Jacqueline A., Papaioannou, Catherine, Cheng, Wan-Jung, Ellett, Anne M., Jacobson, Jonathan C., Purcell, Damian F. J., Wesselingh, Steve L., Gorry, Paul R., Lewin, Sharon R., Churchill, Melissa J.
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - virology; Azepines - pharmacology; Biomedical and Life Sciences; Biomedicine; Cell Line; Cell Survival - drug effects; Depsipeptides - pharmacology; Disulfiram - pharmacology; Fetus; Histone Deacetylase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - metabolism; Humans; Hydroxamic Acids - pharmacology; Immunology; Indoles - pharmacology; Infectious Diseases; Lentivirus; Macrophages - drug effects; Macrophages - metabolism; Macrophages - virology; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - virology; Neurosciences; Piperazines - pharmacology; Primary Cell Culture; Retroviridae; Transcription, Genetic - drug effects; Triazoles - pharmacology; Virology; Virus Activation - drug effects; Virus Activation - genetics; Virus Latency - drug effects; Virus Latency - genetics; Virus Replication - drug effects; Virus Replication - genetics
• ISSN: 1355-0284; 1538-2443
• DOI: 10.1007/s13365-015-0413-4

Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.