Will the cognitive benefits of JAK inhibition in HAND translate from mouse models to HIV-positive humans on cART?

neuroinflammation open
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Priority
87%
Importance
90%
Tractability
85%
Market price
50%

Description

While the authors reference safety data from ruxolitinib trials, the efficacy of baricitinib for reversing cognitive deficits in human HAND patients remains untested. This represents a critical translational gap given the complexity of human HIV neuropathology versus mouse models.

Gap type: open_question Source paper: Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro. (2019, Journal of neuroinflammation, PMID:31561750)

Resolution criteria

Resolution requires: (1) head-to-head comparison of JAK inhibitors (tofacitinib, baricitinib) vs vehicle in HAND mouse model (HIV-1 transgenic or infected mice) measuring cognitive outcomes (Morris water maze, operant conditioning) and viral load; (2) demonstration that JAK inhibition reduces neuroinflammation (Iba1, CD68, cytokines) and improves synaptic markers (synaptophysin, PSD95); (3) PK study establishing brain penetration at effective doses. Mouse behavioral improvement without mechanistic understanding is insufficient.

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