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Targeting Immunometabolism: a novel role for itaconate in the treatment of HIV-associated neurocognitive disorder and cocaine use disorder

Award Number: R21DA058586
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $181,708 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Drug Abuse and Addiction Research Programs	000	2	5/7/2024	NON-COMPETING CONTINUATION	$181,708
														Subtotal = $181,708

Issue Date FY: 2023 ( Subtotal = $219,090 )
2023	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Abuse and Addiction Research Programs	000	1	4/3/2023	NEW	$219,090
														Subtotal = $219,090

Grand Total All Awards = $400,798

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Targeting Immunometabolism: a novel role for itaconate in the treatment of HIV-associated neurocognitive disorder and cocaine use disorder

Award Number: R21DA058586

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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