The effects of JAK inhibitors in a mouse model of HIV neurocognitive disorders

Objective: The benefits of ruxolitinib, a JAK inhibitor, on HIV encephalitis (HIVE) histopathology in our HIV associated neurocognitive disorders (HAND) mouse model are reviewed and new studies presented using baricitinib. We hypothesized that baricitinib would cross the blood brain barrier (BBB) in HAND mice and reverse behavioral abnormalities assessed by object recognition testing (ORT). Background: HAND occurs in 50% of HIV patients despite combined antiretroviral therapy (cART). Adjunctive therapies must be devised. A model of HAND in SCID mice was used to investigate novel therapeutics on HIVE and associated behavioral abnormalities. Previously ruxolitinib, a JAK inhibitor, administered subcutaneously (SC), crossed the BBB and improved HIVE. Baricitinib is a JAK inhibitor approved for rheumatoid arthritis, but with improved pharmacokinetics and greater potency allowing lower and once a day dosing. Design/Methods: SCID mice were injected intracerebrally (IC) with HIV-infected or uninfected human macrophages. Groups (n=9) of mice included controls, HAND mice treated with SC with saline, HAND mice given baricitinib SC qday (10 mg/kg) and baricitinib SC qday (50 mg/kg). On day 5 after IC injection of cells mice began ORT. On day 6 after the first ORT set, mice were started on treatments. They were retested on days 12 and 13, sacrificed (brain extraction) for FACS analyses. Results: Baricitinib was detected in brains using mass spectrometry. Abnormal ORT in HAND mice (days 5 and 6) was reversed (days 12 and 13) by low and high dose baricitinib. FACS revealed that baricitinib reduced activated brain macrophages and p24 + human cells in brain. Conclusions: JAK 1/2 inhibitors are able to the BBB and reverse HAND behavioral abnormalities and brain pathological features of HIVE in mice. Baricitinib is a particularly attractive agent based on its pharmacokinetic features as an add on [to cART] agent. These preclinical data support consideration of a Phase I/II trial in humans with HAND. Study Supported by: Study supported by VA Merit 1101BX001506-01A2 (Tyor, PI) and 1R01-MH100999 (Schinazi and Tyor, PIs). Disclosure: Dr. Tyor has nothing to disclose. Dr. Haile has nothing to disclose. Dr. Gavegnano has nothing to disclose. Dr. Bimonte-Nelson has nothing to disclose. Dr. Koneru has nothing to disclose. Dr. Schinazi has nothing to disclose.