HIV Associated Neurocognitive Disorder (HAND) is one of the most common and clinically important complications of HIV infection. There is an urgent need for effective therapeutic strategies for HAND exacerbated by Cocaine Use Disorder (CUD). Through an extensive analysis of the HIV-induced transcriptome, we determined that HIV and cocaine profoundly induce overexpression of the microglia-specific gene aconitate decarboxylase 1 (acod1). Acod1 converts the tricarboxylic acid (TCA) intermediate cis-aconitate to itaconate during inflammation. Itaconate activates anti-inflammatory transcription factors thereby protecting macrophages from infection-triggered cell death. Although the attenuation of inflammation by itaconate has been characterized in peripheral macrophages, the role of immunometabolism, including itaconate production, has not been studied in HIV and cocaine-exposed microglia. This innovative proposal will characterize novel targets of itaconate action in the brain. The hypothesis of this proposal is that itaconate balances neuroinflammation by activating anti-inflammatory pathways in HIV-infected microglia cells, consequently cell death is attenuated allowing microglial HIV reservoirs to be maintained. Further, we hypothesize that inhibition of itaconate synthesis and downstream pathways in HIV-infected microglia has the potential to selectively eliminate HIV reservoirs in the brain tissues – i.e., an innovative “Non-activating Shock and Kill” cure approach. In contrast, we will also explore the strong anti-inflammatory potential of the cell- and blood-brain barrier (BBB)-penetrating modified derivatives of itaconate -- dimethyl Itaconate (DMI) and 4-octyl-itaconate. Our preliminary results show that 4-octyl-itaconate protects primary neurons from HIV-tat and cocaine toxicity. Thus sustained activation of itaconate pathways by BBB-penetrable itaconate derivatives may be an alternative approach for the treatment of HAND worsened by CUD. This innovative proposal employs a novel approach centered on immunomeabolism that has not been considered in targeting HIV-infected microglia. Esters of other metabolites, including fumarate, are already approved for inflammatory diseases such as psoriasis and arthritis, increasing the clinical relevance of these exciting studies.