The Janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model

• Authors: Woldeab B. Haile, Veterans Affairs Medical Center; Christina Gavegnano, Emory University; Sijia Tao, Emory University; Yong Jiang, Emory University; Raymond Schinazi, Emory University; William Tyor, Emory University
• Journal Title: Neurobiology of Disease
• Volume: Volume 92, Number Pt B
• Publisher: Elsevier | 2016-08, Pages 137-143
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.nbd.2016.02.007
• Subjects: Biology, Virology; Biology, Neuroscience; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SCID MICE; INTERFERON-ALPHA; COGNITIVE DYSFUNCTION; MOUSE MODEL; ACTIVATION; BRAIN; ABNORMALITIES; MYELOFIBROSIS

Abstract

A hallmark of persistent HIV-1 infection in the central nervous system is increased activation of mononuclear phagocytes and surrounding astrogliosis, conferring persistent HIV-induced inflammation. This inflammation is believed to result in neuronal dysfunction and the clinical manifestations of HIV-associated neurocognitive disorders (HAND). The Jak/STAT pathway is activated in macrophages/myeloid cells upon HIV-1 infection, modulating many pro-inflammatory pathways that result in HAND, thereby representing an attractive cellular target. Thus, the impact of ruxolitinib, a Janus Kinase (Jak) 1/2 inhibitor that is FDA approved for myelofibrosis and polycythemia vera, was assessed for its potential to inhibit HIV-1 replication in macrophages and HIV-induced activation in monocytes/macrophages in culture. In addition, a murine model of HIV encephalitis (HIVE) was used to assess the impact of ruxolitinib on histopathological features of HIVE, brain viral load, as well as its ability to penetrate the blood-brain-barrier (BBB). Ruxolitinib was found to inhibit HIV-1 replication in macrophages, HIV-induced activation of monocytes (CD14/CD16) and macrophages (HLA-DR, CCR5, and CD163) without apparent toxicity. In vivo, systemically administered ruxolitinib was detected in the brain during HIVE in SCID mice and markedly inhibited astrogliosis. Together, these data indicate that ruxolitinib reduces HIV-induced activation and infiltration of monocytes/macrophages in vitro, reduces the replication of HIV in vitro, penetrates the BBB when systemically administered in mice and reduces astrogliosis in the brains of mice with HIVE. These data suggest that ruxolitinib will be useful as a novel therapeutic to treat humans with HAND.