Mechanisms of Reciprocal Interactions between HIV Associated Neuroinflammation and CNS Persistence: Implications in HIV Neuropathogenesis and Cure (R01 Clinical Trial Not Allowed) | RFA MH 25 180

Opportunity Information: Apply for RFA MH 25 180

The National Institutes of Health (NIH) is soliciting research applications for an R01 grant opportunity titled "Mechanisms of Reciprocal Interactions between HIV Associated Neuroinflammation and CNS Persistence: Implications in HIV Neuropathogenesis and Cure (R01 Clinical Trial Not Allowed)" under funding opportunity number RFA-MH-25-180. This discretionary grant focuses on basic and translational research that clarifies how HIV-related inflammation in the central nervous system (CNS) and the persistence of HIV within CNS tissues influence one another, particularly in people who otherwise have excellent control of HIV in the blood due to effective antiretroviral therapy. A key theme is that even when systemic viral loads are well suppressed, HIV can remain in CNS-associated cellular reservoirs and may be linked to ongoing immune activation, inflammatory signaling, and neurologic complications; the initiative is designed to push the field toward a more mechanistic, experimentally grounded understanding of these bidirectional relationships and how they matter for both neuropathogenesis and HIV cure strategies.

Scientifically, the opportunity emphasizes modern experimental approaches that can directly interrogate CNS-relevant biology rather than relying only on peripheral measurements. NIH is specifically encouraging the use of novel CNS cell systems, organoid models, and single-cell technologies. In practical terms, that means projects may be expected to leverage advanced in vitro or ex vivo platforms that better mimic human brain microenvironments (such as brain organoids, assembloids, microphysiological systems, or other sophisticated neural-glial co-culture models), along with single-cell or spatially resolved profiling methods (for example, single-cell RNA sequencing, single-nucleus approaches, multi-omics, or other high-resolution technologies) to map viral persistence, inflammatory cell states, and cell-to-cell signaling networks. The intention is to capture the complexity of CNS cell types and their interactions (neurons, astrocytes, microglia, oligodendrocytes, perivascular macrophages, endothelial cells, and infiltrating immune cells) and to pinpoint mechanistic pathways by which HIV persistence and neuroinflammation sustain or amplify one another despite strong virologic suppression.

The initiative is framed around reciprocal interactions, meaning applications should not only look at how HIV persistence can trigger or maintain neuroinflammatory responses, but also how neuroinflammation and immune signaling within the CNS might promote viral survival, latency, reactivation potential, or reservoir stability. This could include studying how inflammatory cytokines, chemokines, interferon-stimulated pathways, glial activation programs, blood-brain barrier alterations, or metabolic stress states influence HIV infection dynamics in CNS-relevant cells, and conversely how viral products, low-level expression, or infected-cell signatures reshape CNS immune environments. The long-term relevance is tied to understanding HIV-associated neurologic disease mechanisms and to informing cure-related interventions by identifying CNS-specific barriers, risks, or therapeutic targets that might otherwise be missed if cure strategies are evaluated only in peripheral compartments.

From an administrative standpoint, this is an NIH research grant (Funding Instrument Type: Grant; Activity: R01) and it explicitly does not allow clinical trials, indicating the funded work should remain within non-clinical-trial research boundaries. The opportunity sits within NIH health and education-related funding activity categories and is associated with CFDA numbers 93.242, 93.279, and 93.853. The original application closing date listed is 2024-11-08, and the posting indicates the opportunity was created on 2024-06-14. While the notice provided does not specify an award ceiling or the expected number of awards, applicants would typically plan an R01-style project with clear aims, strong mechanistic rigor, and an approach that matches the initiative's emphasis on advanced CNS modeling and high-resolution analytic methods.

Eligibility is broad and includes many U.S. organization types 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; public housing authorities/Indian housing authorities; Native American tribal organizations that are not federally recognized; 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 opportunity also highlights additional eligible applicant categories, 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, and U.S. territories or possessions. Importantly, non-domestic (non-U.S.) entities (foreign organizations) are eligible to apply, non-domestic components of U.S. organizations are eligible, and foreign components (as defined by the NIH Grants Policy Statement) are allowed, signaling that NIH is open to international participation and cross-border collaborations when scientifically justified.

In summary, this R01 opportunity is aimed at advancing the HIV neuroscience and cure fields by funding mechanistic studies that dissect how CNS HIV persistence and neuroinflammation reinforce each other in the context of effective systemic viral suppression. It is designed to accelerate work that uses next-generation CNS models and single-cell level tools to generate actionable insights into HIV neuropathogenesis and to clarify what CNS reservoirs and inflammatory circuits may mean for safe and durable HIV cure approaches, while remaining outside the scope of clinical trial research.

• 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 (R01 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.

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