HIV infection frequently results in varying degrees of neurocognitive and functional impairment, collectively termed HIV-associated neurocognitive disorders (HAND). Pharmaceutical interventions for HAND have had very limited success. Based on results of large-scale transcriptomic analyses in human samples and in vitro studies of HIV neuropathogenesis, antioxidant inflammation modulators that modify the nrf2/KEAP1 axis may be effective for the prevention and/or treatment of HAND. Our preliminary data show one such compound, Bardoxolone, is effective in reducing HIV replication in human monocytes and macrophages, as well as increasing neuroprotective factors in neurons and macrophages. However, before moving forward with a costly and labor intensive clinical trial, it is important to further characterize the safety and efficacy of Bardoxolone for treating and/or preventing HAND. We propose three studies. First, we will examine the ability of Bardoxolone to mitigate HIV-related cognitive-behavioral deficits in HIV-infected humanized NOG mice. Second, we assess the efficacy of Bardoxolone in reducing viral replication and HIV-induced inflammatory factors in plasma of the humanized mice. Finally, we examine brain tissue of the same humanized mice to determine if Bardoxolone mitigates HIV-induced neural injury and increases expression of neuroprotective factors. Results of these experiments will provide a strong foundation to proceed with an Investigational New Drug application to the FDA and ultimately clinical trials.

Public Health Relevance

to Health HIV infection frequently results in neurocognitive impairment and deficits in day-to-day functioning, however, treatments thus far have been ineffective. Here we build upon promising preliminary data to generate preclinical data on the safety and efficacy of a novel compound (Bardoxolone) for the prevention and treatment of HIV-associated neurocognitive disorders. For this, we bridge expertise across several labs to assess behavioral, immunological, and histological effects of Bardoxolone in a HIV-infected humanized mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH115825-02
Application #
9773222
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Colosi, Deborah
Project Start
2018-09-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095