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

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.

• Authors: Woldeab B Haile, Christina Gavegnano, Sijia Tao, Yong Jiang, Raymond F Schinazi, William R Tyor
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 92 Issue Pt B Pg. 137-43 (08 2016) ISSN: 1095-953X [Electronic] United States
• PMID: 26851503 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Janus Kinase Inhibitors
• Nitriles
• Pyrazoles
• Pyrimidines
• ruxolitinib
• Tenofovir

Topics

• Animals
• Antiviral Agents (pharmacology)
• Astrocytes (drug effects, metabolism, pathology, virology)
• Blood-Brain Barrier (drug effects, metabolism, virology)
• Disease Models, Animal
• Encephalitis, Viral (drug therapy, metabolism, pathology)
• Gliosis (drug therapy, metabolism, pathology, virology)
• HIV Infections (drug therapy, metabolism, pathology)
• HIV-1 (drug effects, physiology)
• Humans
• Janus Kinase Inhibitors (pharmacology)
• Macrophages (drug effects, virology)
• Male
• Mice
• Monocytes (drug effects, virology)
• Nitriles
• Pyrazoles (pharmacology)
• Pyrimidines
• Tenofovir (pharmacology)
• Virus Replication (drug effects)