Microglial Pathophysiology in Comorbid Substance Use Disorder (SUD) and HIV (R61/R33 Clinical Trial Not Allowed) | RFA DA 25 063

Opportunity Information: Apply for RFA DA 25 063

The funding opportunity titled "Microglial Pathophysiology in Comorbid Substance Use Disorder (SUD) and HIV (R61/R33 Clinical Trial Not Allowed)" (Funding Opportunity Number RFA-DA-25-063) is a National Institutes of Health (NIH) discretionary grant focused on neuroimmune mechanisms at the intersection of HIV infection and substance use disorder. Its central purpose is to push the field beyond broad, whole-brain or mixed-cell signals by producing highly specific molecular maps of microglia, the brain's resident immune cells, under conditions where HIV and SUD occur together. The intent is not just descriptive profiling, but using those data to build interaction networks and then test mechanistic hypotheses about how HIV-harboring microglia may drive or worsen the types of neurological damage and dysfunction that appear in people living with both HIV and SUD.

Scientifically, the announcement is aimed at generating brain region- and cell-type-specific microglial protein profiles in the context of HIV and SUD. That emphasis on protein profiles matters because proteins are closer to functional biology than gene expression alone: they reflect signaling activity, immune activation states, metabolic shifts, synaptic remodeling, and other processes that microglia use to influence neurons and brain circuits. By specifying brain region and cell type, the opportunity highlights that microglial behavior is not uniform across the brain, and that relevant disease mechanisms may be localized to particular circuits affected by HIV and commonly used substances. The expected outcome is a set of molecular profiles that can be translated into interaction networks (for example, pathways and protein-protein relationships) that clarify which microglial processes are most disrupted or most causally linked to neuropathology in comorbidity.

A key second step in the program is mechanistic work that leverages the generated profiles and networks to establish how HIV-harboring microglia contribute specifically to neuropathologies encountered with comorbid HIV and SUD. In practical terms, this means applicants are expected to move from identifying patterns to explaining cause-and-effect, such as pinpointing microglial pathways that become uniquely harmful when both HIV-related factors and substance-related exposures are present. The focus on "HIV-harboring microglia" suggests interest in persistence of HIV in the central nervous system, microglia as a potential reservoir, and how that reservoir status might alter inflammatory signaling, synaptic pruning, neuronal support functions, or responses to drugs of abuse in ways that amplify cognitive, behavioral, or neurodegenerative outcomes.

From a mechanism and structure standpoint, this is an R61/R33 phased innovation award and it explicitly states "Clinical Trial Not Allowed." The R61/R33 format typically supports a milestone-driven progression where an initial phase (R61) establishes feasibility, generates key datasets, or proves an approach, and a second phase (R33) expands and deepens the work once predefined benchmarks are met. Even without going into specific milestone language from the full FOA text, the overall design implies a pipeline: first build the region- and cell-type-resolved microglial proteomic resources in HIV/SUD contexts, then use those resources to validate networks and test mechanisms with rigorous experimental approaches. The clinical trial restriction indicates the funded research should not be structured as a prospective interventional study in humans designed to evaluate health outcomes, though it can still support many forms of non-trial human-based research depending on NIH definitions (for instance, analysis of existing specimens, observational studies, or laboratory-based investigations).

Administratively, the opportunity is categorized under Education and Health funding activity and is associated with CFDA number 93.279. The agency is the NIH, and the original closing date is listed as 2025-08-14. The public listing does not specify an award ceiling or the expected number of awards, which usually means applicants need to consult the full FOA for budget guidance, anticipated award counts, and any institute-specific limits or preferences.

Eligibility is broad and intentionally inclusive, spanning government entities, academic institutions, nonprofits, and the private sector. Eligible applicants include state, county, city or township governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; public housing authorities and Indian housing authorities; Native American tribal governments (federally recognized) as well as Native American tribal organizations that are not federally recognized; nonprofits with and without 501(c)(3) status (excluding institutions of higher education in those nonprofit categories); for-profit organizations other than small businesses; and small businesses. In addition to these standard categories, the announcement explicitly calls out other eligible applicant types such as 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 federal agencies, U.S. territories or possessions, regional organizations, and non-domestic (non-U.S.) entities (foreign organizations). That expanded list signals an interest in encouraging participation from a wide range of institutions and communities, including those that may be closely connected to populations disproportionately affected by HIV and substance use, as well as organizations that can contribute unique resources, cohorts, tissue repositories, analytic platforms, or specialized neuroscience and proteomics expertise.

In summary, this NIH grant opportunity is designed to produce detailed, region- and cell-type-resolved microglial proteomic datasets in HIV and SUD comorbidity and to use those datasets to build and validate interaction networks that explain disease mechanisms. It prioritizes mechanistic insight into how microglia that harbor HIV could contribute to the neurological complications seen when HIV and SUD co-occur, using a phased R61/R33 structure to move from feasibility and resource generation to deeper mechanistic testing, while keeping the work outside the boundaries of NIH-defined clinical trials.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Microglial Pathophysiology in Comorbid Substance Use Disorder (SUD) and HIV (R61/R33 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 2024-08-23.
• Applicants must submit their applications by 2025-08-14. (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.

Apply for RFA DA 25 063

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