The National Institute on Drug Abuse (NIDA) is soliciting applications for research on the role of inflammasome activation in the context of HIV-1 infection and substance use, particularly in relation to neurocognitive disorder (NCD) and immune function. This funding opportunity (R01 Clinical Trial Not Allowed), reissued under RFA-DA-25-069, aims to explore the mechanisms underlying inflammasome-mediated neuroinflammation and immune responses in HIV-positive individuals with substance use disorders (SUDs). The research will focus on understanding how inflammasome activation triggered by HIV and addictive drugs contributes to neurocognitive impairment and disease progression, with the goal of informing therapeutic strategies to improve clinical outcomes in this population.

The program invites applications for basic and preclinical studies that investigate inflammasome pathways within the central nervous system (CNS) and their interactions with various CNS cell types, particularly myeloid cells. Studies may examine the effects of addictive substances such as opioids, stimulants, and cannabinoids, among others, on inflammasome activation, and the role of myeloid cell-triggered inflammasomes in HIV infection and CNS-related outcomes. The research areas include characterizing inflammasome activation across different brain regions, understanding inflammasome expression in resident CNS cells, and exploring the impact of substance use on myeloid cell-mediated inflammation in the CNS.

Projects responsive to this Notice of Funding Opportunity (NOFO) should address HIV and substance use jointly, as proposals studying only HIV infection or only the effects of addictive substances will not be considered. Applications focused solely on alcohol use and HIV will also be excluded. Successful applications should explore inflammasome activation and its potential as a biomarker for neuroinflammation, mechanisms of inflammation on cognition and behavior, and pharmacological interventions to modulate inflammasome pathways in this population. Proposals that address B cell perturbations, antiretroviral therapy impacts, and myeloid cell-related immune responses in the context of HIV and SUDs are encouraged.

The program will fund up to four awards across this R01 NOFO and its R21 exploratory/developmental companion RFA-DA-25-068, with a total budget of $2 million for FY 2026. Budgets are limited to $500,000 in direct costs per year, and the project duration may be up to five years. Eligible applicants include higher education institutions, nonprofit and for-profit organizations, government bodies, and foreign entities. Each applicant institution must complete registrations with SAM, eRA Commons, and Grants.gov before submission.

Applications will be reviewed for their significance, innovation, rigor, and feasibility, with emphasis on the investigator's expertise and resources. Evaluation will include protections for human subjects, where applicable, as well as the relevance of vertebrate animal protocols and biohazard safety measures. Applications should present clear rationale and a well-designed approach to studying the interaction of inflammasomes, HIV, and substance use. After initial peer review by a NIDA-convened Scientific Review Group, selected applications will undergo further evaluation by the National Advisory Council on Drug Abuse.

Applications open on February 13, 2025, with a due date of March 13, 2025. The earliest anticipated start date for funded projects is December 2025. Key contacts for scientific, peer review, and financial questions are listed in the NOFO, and prospective applicants are encouraged to submit a non-binding letter of intent by February 13, 2025, to assist NIDA in planning for the review process.