Advancing Research on Molecular Targets and Mechanisms that Influence the Interplay Between Sex Hormones, HIV, and Addictive Substances (R21 Clinical Trials Not Allowed) | RFA DA 26 008

Opportunity Information: Apply for RFA DA 26 008

The National Institutes of Health (NIH) is soliciting R21 grant applications under the opportunity titled "Advancing Research on Molecular Targets and Mechanisms that Influence the Interplay Between Sex Hormones, HIV, and Addictive Substances (R21 Clinical Trials Not Allowed)" (Funding Opportunity Number: RFA-DA-26-008; CFDA: 93.279). The core goal is to support early-stage, exploratory research that pinpoints and explains molecular and biological mechanisms through which sex hormones shape the health consequences that arise when HIV and substance use occur together. A major emphasis is on moving beyond describing associations and instead clarifying mechanisms and molecular targets that could eventually inform therapeutic strategies for HIV and substance use disorder (SUD) comorbidity. Clinical trials are not allowed under this R21, meaning proposed work should focus on mechanistic, preclinical, or non-trial human studies rather than testing interventions in a clinical trial framework.

Scientifically, the NOFO is centered on the intersection of three factors that often interact in real-world patient populations: sex hormones (and the broader endocrine milieu), HIV infection and its downstream immune and neurological effects, and exposure to addictive substances. The intent is to fund studies that delineate how sex hormones may influence HIV-related outcomes in the context of drug use, and conversely how substance exposure and HIV may interact with hormone-driven pathways. In practical terms, this can include investigating how hormone signaling affects viral persistence, immune activation, inflammation, neurocognitive outcomes, reward and stress circuitry, or other biological systems that are commonly implicated in both HIV pathophysiology and addiction biology. The opportunity also encourages applicants to use mechanistic insights to identify or explore biological pathways as potential therapeutic targets, laying groundwork for future intervention development even though intervention trials themselves are outside the scope of this announcement.

A key compliance requirement is the mandatory inclusion of a Plan for Enhancing Diverse Perspectives (PEDP). This plan is not optional and will be evaluated during scientific and technical peer review. Applications submitted without a PEDP will be considered incomplete and will be withdrawn before review, so applicants need to treat this as a core component of the proposal rather than an add-on. The PEDP is meant to show, in concrete and credible terms, how the project will incorporate diverse perspectives in ways that strengthen the science. Depending on the project, that can relate to research team composition, stakeholder engagement, partnerships, scientific viewpoints, methodological approaches, or considerations relevant to populations affected by HIV and SUD.

From an administrative standpoint, this is a discretionary grant mechanism using the NIH R21 activity code, which is typically designed for exploratory or developmental projects that generate proof-of-concept data, clarify feasibility, or open new lines of investigation. The agency is NIH, and the activity category listed for the opportunity is Education and Health. The original application due date is March 13, 2025. An award ceiling is not specified in the provided source information, and the expected number of awards is also not listed, so applicants would need to consult the full NOFO text for any budget caps, project period limits, and institute-specific expectations.

Eligibility is broad and includes many types of U.S. entities, such as state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; tribal organizations that are not federally recognized; public housing authorities/Indian housing authorities; nonprofits with and without 501(c)(3) status (other than institutions of higher education); for-profit organizations other than small businesses; and small businesses. The NOFO also explicitly highlights additional eligible applicants and organizational types that NIH aims to ensure are welcomed in the competition, 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 federal agencies, regional organizations, U.S. territories or possessions, and even non-U.S. entities (foreign organizations). This wide eligibility reflects the public health importance of HIV-SUD comorbidity and the value of bringing in varied institutional strengths, community connections, and scientific expertise.

Overall, this opportunity is aimed at sharpening the mechanistic understanding of how sex hormone biology intersects with HIV and addictive substances, with the expectation that well-justified mechanistic findings can reveal actionable molecular targets. The NIH is signaling that strong proposals will not only ask important biological questions, but will also be intentional about incorporating diverse perspectives through a required PEDP, and will stay within scope for an R21 that does not include clinical trials.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Advancing Research on Molecular Targets and Mechanisms that Influence the Interplay Between Sex Hormones, HIV, and Addictive Substances (R21 Clinical Trials 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 2024-08-15.
• Applicants must submit their applications by 2025-03-13. (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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