Combined treatment of adenosine nucleoside inhibitor NITD008 and histone deacetylase inhibitor vorinostat represents an immunotherapy strategy to ameliorate West Nile virus infection

• Published in: Antiviral research 2015-10, Vol.122, p.39-45
• Main Authors: Nelson, Jacob, Roe, Kelsey, Orillo, Beverly, Shi, Pei-Yong, Verma, Saguna
• Format: Article
• Language: English
• Subjects: Adenosine - administration & dosage; Adenosine - analogs & derivatives; Adenosine - therapeutic use; Adenosine analogue inhibitor; Animals; Antiviral; Brain - immunology; Brain - pathology; Brain - virology; Cercopithecus aethiops; Chemokine CCL3 - immunology; Co-treatment; Dengue virus; Drug Therapy, Combination; Flaviviridae; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - therapeutic use; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - therapeutic use; Inflammation; Mice; Tumor Necrosis Factor-alpha - immunology; Vero Cells; Virus Replication - drug effects; West Nile Fever - drug therapy; West Nile Fever - immunology; West Nile Fever - prevention & control; West Nile virus; West Nile virus - drug effects; West Nile virus - growth & development; West Nile virus - immunology
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2015.07.008

•NITD008 treatment of WNV-infected mice attenuates viremia, prevents neuroinvasion and completely prevents mortality.•NITD008 loses its protective effect when administered during the CNS phase of the WNV disease.•Co-treatment with histone deacetylase inhibitor and NITD008 improves mortality by reducing inflammation and neuronal death. West Nile virus (WNV), a member of the Flaviviridae family, is the leading cause of viral encephalitis in the United States. Despite efforts to control the spread of WNV, there has been an increase in the number of outbreaks and clinical cases with neurological problems. There are no antiviral compounds currently in trials for WNV. NITD008 is an adenosine analogue inhibitor that interrupts the RNA-dependent RNA polymerase of flaviviruses. Previous studies demonstrated NITD008 as a potent antiviral for dengue virus, however this drug was associated with preclinical toxicity. The ability of NITD008 to block WNV replication is only shown in Vero cells. Neuroinflammation is also a major cause of the WNV-associated pathology, therefore we evaluated the effect of NITD008 and a newly characterized anti-inflammatory drug vorinostat (SAHA), a histone deacetylase inhibitor, on WNV replication and disease progression in a mouse model. When administered at 10 and 25mg/kg at days 1–6 after WNV infection in C57BL/6 mice, NITD008 conferred complete protection from clinical symptoms and death, which correlated with reduced viral load in the serum and restriction of virus-CNS entry. Delay of NITD008 treatment to days 3–6 and days 5–9 after infection, when WNV replication was high in the periphery and brain, resulted in the gradual loss of protection against WNV infection. However, co-treatment with SAHA and NITD008 during the CNS phase of disease improved disease outcome significantly by reducing inflammation and neuronal death. Our results support potential synergistic effect of combination therapy of NITD008 with SAHA for the treatment of WNV encephalitis.