Deciphering Immune-CNS interactions in HIV utilizing in-vitro and in-vivo model systems (R21 Clinical Trial Not Allowed) | RFA MH 21 251

Opportunity Information: Apply for RFA MH 21 251

The funding opportunity titled "Deciphering Immune-CNS interactions in HIV utilizing in-vitro and in-vivo model systems (R21 Clinical Trial Not Allowed)" (Funding Opportunity Number: RFA-MH-21-251) is a discretionary NIH research grant intended to advance understanding of how the immune system and the central nervous system (CNS) interact in people living with HIV who are receiving antiretroviral therapy (ART). Even when HIV is well controlled with ART, many individuals continue to experience neurologic complications, neuroinflammation, or cognitive and behavioral issues that may be linked to persistent immune activation, viral reservoirs, or ongoing inflammatory signaling that affects brain cells and brain function. This initiative targets that gap by encouraging mechanistic research that can clarify what drives immune-CNS communication and dysfunction in the treated HIV setting.

The opportunity uses the R21 mechanism, which is typically designed for early-stage, exploratory, or high-impact pilot studies that can generate strong preliminary data and open up new directions for a field. A key constraint is that clinical trials are not allowed under this announcement. In practical terms, the work should be preclinical and mechanistic rather than interventional studies in humans. The title explicitly emphasizes the use of in-vitro and in-vivo model systems, pointing applicants toward laboratory-based approaches such as cell culture models (including human-derived immune cells, glia, neurons, organoids, co-culture systems, microfluidic or blood-brain barrier models) and animal models that can capture relevant aspects of HIV-associated neuroimmune biology. Projects would be expected to interrogate pathways and interactions that explain how immune activity influences CNS cells, how CNS-resident immune populations respond, and how chronic HIV infection under ART reshapes these relationships over time.

Scientifically, the scope is centered on immune-CNS crosstalk in treated HIV. That can include questions like how peripheral immune activation translates into CNS inflammation, how immune cells traffic across or signal through the blood-brain barrier, how viral persistence or viral proteins might continue to trigger inflammatory cascades, and how microglia, astrocytes, macrophages, and other CNS-resident or infiltrating immune cells contribute to neuronal injury or synaptic dysfunction. It can also encompass identifying cellular and molecular mediators (cytokines, chemokines, interferon responses, inflammasome pathways, complement signaling, extracellular vesicles, and metabolic or epigenetic reprogramming) that sustain neuroinflammatory states even when plasma virus is suppressed. The emphasis on model systems suggests NIH is looking for studies that can disentangle cause-and-effect relationships, test specific hypotheses, and produce measurable mechanistic insights that could later inform biomarker development or therapeutic strategies, without actually conducting a clinical trial in this grant.

Administratively, the sponsor is the National Institutes of Health (NIH), and the funding activity category is Health. The CFDA numbers listed are 93.242 and 93.853, which correspond to NIH funding lines associated with mental health and infectious disease research areas. The opportunity category is listed as discretionary, and the funding instrument is a grant. The original closing date in the source information is 2021-12-07, and the creation date is 2021-08-19. The award ceiling and expected number of awards are not specified in the provided data, which often means applicants would need to consult the full funding announcement or NIH Institute/Center budget guidance for typical R21 limits and expectations.

Eligibility is broad and includes a wide range of domestic applicants: 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 and 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. In addition, the opportunity explicitly calls out several categories of other eligible applicants, 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), eligible federal agencies, faith-based or community-based organizations, U.S. territories or possessions, regional organizations, and non-domestic (non-U.S.) entities (foreign organizations). This breadth signals an intent to encourage participation from diverse institution types and geographies, including international groups with strong relevant model-system expertise.

In summary, this NIH R21 opportunity is focused on foundational, non-clinical-trial research that uses in-vitro and in-vivo models to explain how immune processes interact with the CNS in people living with HIV who are on ART. The central goal is to generate mechanistic clarity about persistent neuroimmune dysfunction in treated HIV, building a stronger biological basis for future translational work, while keeping the funded studies firmly in the preclinical and experimental domain rather than human intervention trials.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Deciphering Immune-CNS interactions in HIV utilizing in-vitro and in-vivo model systems (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): 93.242, 93.853.
• This funding opportunity was created on 2021-08-19.
• Applicants must submit their applications by 2021-12-07. (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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