Mechanisms of Reciprocal Interactions between HIV Associated Neuroinflammation and CNS Persistence: Implications in HIV Neuropathogenesis and Cure (R21 Clinical Trial Not Allowed) | RFA MH 25 181

Opportunity Information: Apply for RFA MH 25 181

This NIH funding opportunity (RFA-MH-25-181) invites applications for R21 exploratory/developmental research projects focused on how HIV-related neuroinflammation and HIV persistence within the central nervous system (CNS) influence each other, even when people have excellent control of the virus (typically meaning strong suppression with antiretroviral therapy). The core idea is that inflammation in the brain and spinal cord may help sustain viral reservoirs, while persistent virus or viral products in the CNS may, in turn, keep inflammatory pathways activated. By pushing for studies that look at this two-way, reinforcing relationship, the program aims to clarify mechanisms that contribute to HIV neuropathogenesis (how HIV leads to neurological injury or dysfunction) and to identify insights that could inform cure strategies, particularly those that must address the CNS as a distinct biological compartment.

The initiative emphasizes modern and innovative experimental approaches rather than traditional clinical intervention trials. Applicants are encouraged to use novel CNS cell systems and next-generation models that better mimic human brain biology, including organoid models and advanced single-cell technologies. In practice, this points toward studies that can dissect complex cellular ecosystems in the CNS, identify which cell types are driving or responding to inflammation, and determine where HIV persists at the level of individual cells or specific microenvironments. Using single-cell or similarly high-resolution methods can help distinguish rare infected or reservoir-harboring cells from broader inflammatory populations, and organoids or engineered co-culture systems can allow controlled testing of hypotheses about how glial cells, neurons, macrophage-lineage cells, and other CNS-associated cell types interact during suppressed infection.

Because this is an R21 mechanism, the funding is designed to support early-stage, high-impact, hypothesis-generating work, feasibility studies, and novel conceptual directions that may be too preliminary for larger R01-scale projects. The listing also specifies "Clinical Trial Not Allowed," meaning the application should not propose a prospective study in which human participants are assigned to receive an intervention to evaluate health-related outcomes. Research may still involve human-derived specimens or observational components depending on the full NIH definition and the specific FOA text, but applicants must ensure the proposed work does not meet NIH’s definition of a clinical trial.

From an administrative standpoint, the opportunity is a discretionary grant offered by the National Institutes of Health, with activity categories spanning education and health and CFDA numbers 93.242, 93.279, and 93.853. The original closing date is listed as November 8, 2024, and the opportunity was created on June 14, 2024. An award ceiling is not specified in the provided source data, and the expected number of awards is also not listed, so prospective applicants would typically confirm budget guidance and program expectations in the full announcement and related NIH policy pages for the R21 mechanism.

Eligibility is broad and includes many types of domestic organizations: state, county, and local governments; special districts; independent school districts; public housing authorities/Indian housing authorities; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized tribal governments; tribal organizations that are not federally recognized; and a range of nonprofit organizations (with or without 501(c)(3) status) that are not institutions of higher education. It also allows for-profit organizations (other than small businesses) and small businesses, as well as an "other" category that can capture additional eligible entities. The announcement explicitly highlights additional eligible applicants, including Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving Institutions, Historically Black Colleges and Universities, Tribally Controlled Colleges and Universities, faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, regional organizations, and non-U.S. (foreign) entities. Taken together, that eligibility language signals an interest in attracting a diverse set of institutions and research environments, potentially including groups that can contribute specialized model systems, unique technical platforms, or distinct perspectives on HIV-related neurological disease.

Overall, the grant’s purpose is to accelerate mechanistic discovery at the intersection of HIV persistence and neuroinflammation in the CNS under conditions of virologic suppression, using cutting-edge experimental systems and cellular-resolution analytic tools. The expected payoff is a clearer, more biologically grounded picture of how CNS reservoirs and inflammatory circuitry maintain each other, and how that feedback loop might be interrupted to reduce neurological harm and remove barriers to durable HIV remission or cure.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Mechanisms of Reciprocal Interactions between HIV Associated Neuroinflammation and CNS Persistence: Implications in HIV Neuropathogenesis and Cure (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, 93.279, 93.853.
• This funding opportunity was created on 2024-06-14.
• Applicants must submit their applications by 2024-11-08. (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 MH 25 181

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