Chemical Probes and Drugs for Modulating HIV Transcription in the Context of Substance Use Disorders (R21 Clinical Trial Not Allowed) | RFA DA 25 008

Opportunity Information: Apply for RFA DA 25 008

The National Institutes of Health (NIH) is soliciting applications under Funding Opportunity Number RFA-DA-25-008, titled "Chemical Probes and Drugs for Modulating HIV Transcription in the Context of Substance Use Disorders (R21 Clinical Trial Not Allowed)." This is a discretionary grant opportunity using the R21 mechanism, which is typically intended to support early-stage, exploratory, and high-impact projects that generate key proof-of-concept data. The scientific focus sits at the intersection of HIV persistence and substance use disorders (SUD), reflecting the reality that HIV infection and substance use frequently occur together and can worsen each other in ways that amplify negative health outcomes.

The core problem this opportunity targets is HIV persistence in reservoirs, including the central nervous system (CNS). Even with effective antiretroviral therapy, HIV can remain in latent or low-activity states within certain cell types and anatomical compartments. When HIV transcription reactivates in these reservoirs, it can contribute to ongoing inflammation and neuropathological complications. In people with SUD, these risks can be heightened because substance use can alter immune responses, brain biology, and other pathways that may influence HIV transcriptional activity and reservoir behavior. This initiative is therefore aimed at advancing strategies that could reduce harm by controlling HIV transcription in the specific biological and clinical context of HIV-SUD comorbidity.

The funding announcement highlights two major research objectives. First, it encourages projects that identify the targets and pathways that can suppress HIV transcriptional activity within HIV reservoirs, explicitly including reservoirs in the CNS, and doing so in ways that are relevant to people who have SUD. This implies an interest in mechanistic work that clarifies how substance use related biological changes may interact with HIV transcriptional regulation, as well as discovery efforts that pinpoint host or viral factors that can be modulated to maintain HIV in a transcriptionally silent state. Second, it seeks applications that apply emerging small-molecule drug discovery approaches to find novel compounds that can function both as pharmacological probes (tools to interrogate biology) and as potential therapeutic leads to suppress HIV transcription in the setting of HIV-SUD comorbidity. In practice, this can include modern hit-finding and optimization strategies, target-based and phenotypic screening, and other chemistry-driven approaches designed to generate new chemical matter that can modulate relevant transcriptional pathways.

A key boundary condition is embedded in the title: "Clinical Trial Not Allowed." That means proposed work must stay on the non-clinical side, such as discovery, preclinical validation, mechanistic studies, and development of chemical probes and early drug candidates, rather than testing interventions in human participants as clinical trials. Applicants should shape projects accordingly, focusing on foundational discoveries and preclinical evidence that can later support translational steps through other mechanisms.

Eligibility is broad and includes many organizational types across government, academia, nonprofit, and industry. Eligible applicants include state, county, city or township, and special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; Native American tribal governments (federally recognized); Native American tribal organizations (other than federally recognized tribal governments); public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status (other than institutions of higher education); for-profit organizations (other than small businesses); and small businesses. The announcement also explicitly notes additional eligible applicant categories such as Historically Black Colleges and Universities (HBCUs), Hispanic-serving institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISISs), along with faith-based or community-based organizations, eligible federal agencies, regional organizations, U.S. territories or possessions, and non-U.S. entities (foreign organizations). This wide eligibility signals a desire to attract interdisciplinary teams, including those with strengths in HIV biology, neuroscience, addiction science, medicinal chemistry, pharmacology, and chemical biology.

Administratively, the opportunity is listed under CFDA number 93.279 and is categorized under education and health funding activities, consistent with NIH research support. The original closing date provided is 2024-08-13, and the opportunity record indicates it was created on 2023-12-20. The provided summary does not include an award ceiling or expected number of awards, suggesting applicants should consult the full notice for budget expectations and program-specific constraints, but the R21 mechanism generally aligns with smaller, time-limited projects intended to rapidly test innovative ideas and generate decisive data.

Overall, this program is best read as a call for innovative, chemically enabled research that can reveal new levers controlling HIV transcription, especially in hard-to-treat reservoirs like the CNS, while explicitly accounting for the biological complications introduced by substance use disorders. The strongest applications will likely connect substance use relevant mechanisms to HIV transcriptional regulation, propose credible discovery and validation plans for small-molecule modulators, and deliver chemical probes or early drug-like candidates that can be used to deepen understanding and set the stage for future translational development.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Chemical Probes and Drugs for Modulating HIV Transcription in the Context of Substance Use Disorders (R21 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 2023-12-20.
• Applicants must submit their applications by 2024-08-13. (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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