Ex Vivo Models for Studies at the Intersection of HIV and Addictive Substance Use (R01 Clinical Trial Not Allowed) | RFA DA 25 074

Opportunity Information: Apply for RFA DA 25 074

This funding opportunity, RFA-DA-25-074, is a National Institutes of Health (NIH) R01 grant competition focused on improving the biological understanding of HIV-associated neurological disorders (HAND) in the context of addictive substance use. The central goal is to support research that can explain how HIV-related processes and exposure to addictive substances interact to drive brain and nervous system dysfunction, with a strong preference for mechanistic, experimentally rigorous studies rather than descriptive work. A key feature of the announcement is its emphasis on ex vivo human cell-based model systems, specifically platforms derived from human induced pluripotent stem cells (hiPSCs), to recreate and study relevant neurobiological and neuroimmune processes under controlled laboratory conditions.

The scientific scope targets the intersection of neuroimmune activity and neuronal-glial pathophysiology. In practical terms, NIH is looking for projects that can dissect how neurons, glial cells (such as astrocytes and oligodendrocytes), and immune-like cells in the brain (including microglia or microglia-like populations, depending on the model) influence each other when HIV-related factors and addictive substances are present. The NOFO highlights interest in work that connects events across biological scales, meaning research that can trace effects from single-cell changes (for example, altered gene expression or immune activation states) up to multicellular interactions and, ideally, neural circuit-level consequences (for example, network activity changes in organoids or engineered neural systems). The emphasis on neuroglial interactions and neuroimmune cell activities signals that proposals should go beyond neuron-only systems and instead incorporate relevant supporting and immune-responsive cell types to model the complexity that underlies HAND.

Methodologically, the opportunity places special weight on unbiased and reproducible analysis, with explicit mention of genetics and epigenetics. That language points to approaches such as single-cell profiling, multi-omics, epigenomic mapping, and other systematic discovery-oriented strategies, provided they are paired with strong experimental design, appropriate controls, and a clear plan to ensure results are robust and replicable. Applicants are being encouraged to use hiPSC-derived ex vivo culturing platforms as a way to control genetic background, manipulate exposures, and measure cellular and molecular outcomes with precision. The reference to addictive substances indicates that the studies should incorporate relevant drugs of abuse or addiction-related compounds as experimental variables, examining how they modify HIV-related neurobiological mechanisms rather than treating substance use as a peripheral factor.

From an administrative standpoint, this is an R01 mechanism and is explicitly labeled “Clinical Trial Not Allowed,” which means the supported work must be non-clinical-trial research. In other words, the projects should be preclinical or basic/translational in nature, centered on ex vivo human-derived model systems rather than testing interventions in human participants. The funding instrument is a grant, the opportunity category is discretionary, and it falls under the health-related activity area (CFDA 93.279). The listed original application due date is 2025-08-13. An award ceiling is not specified in the provided source data, and the expected number of awards is also not specified there.

Eligibility is broad and includes many types of domestic U.S. applicants such as state, county, and local governments; public and private institutions of higher education; independent school districts; special district governments; federally recognized tribal governments; public housing authorities/Indian housing authorities; nonprofits (both 501(c)(3) and non-501(c)(3)); for-profit organizations other than small businesses; and small businesses, among others. The announcement also explicitly calls out additional eligible applicants that NIH wants to encourage, including Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible agencies of the federal government, regional organizations, U.S. territories or possessions, and certain tribal governments and tribal organizations that may not be federally recognized. Notably, non-domestic (non-U.S.) entities (foreign organizations) are also listed as eligible, which is not always the case for every NIH opportunity and suggests NIH is open to strong international expertise in hiPSC platforms, neuroimmune biology, and addiction-HIV intersection research.

Overall, the opportunity is aimed at teams that can build or leverage sophisticated hiPSC-derived ex vivo neural and neuroimmune models, expose those systems to HIV-relevant factors and addictive substances, and generate reproducible, mechanistic insights into how HAND develops and persists. The ideal application will read like a tightly integrated experimental plan: a clear biological question at the HIV-addiction intersection, an ex vivo hiPSC-based platform that captures key human cell types and interactions, and an unbiased but well-controlled analytical strategy that can connect molecular and cellular findings to functional outcomes at higher levels of neural organization.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Ex Vivo Models for Studies at the Intersection of HIV and Addictive Substance Use (R01 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.279.
• This funding opportunity was created on 2024-12-30.
• Applicants must submit their applications by 2025-08-13. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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