Pilot Studies of Biological, Behavioral and Social Mechanisms Contributing to HIV Pathogenesis Within the Mission of NIDDK (R21 Clinical Trial Not Allowed) | PAR 25 068

Opportunity Information: Apply for PAR 25 068

This NIH funding opportunity (PAR-25-068) supports R21 pilot projects focused on HIV pathogenesis in areas that fall squarely within the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The emphasis is on innovative, early-stage basic and translational research that can generate proof-of-concept data, open up new mechanistic directions, or establish feasibility for larger future studies. Clinical trials are not allowed under this announcement, so the work should be designed around discovery science, mechanistic studies, preclinical or translational approaches, and human-focused research that does not meet NIH’s definition of a clinical trial.

Scientifically, the NOFO is tied to the NIH-wide HIV/AIDS research priorities maintained by the NIH Office of AIDS Research (OAR), most recently summarized in NOT-20-018. Applicants are expected to align their projects with those priorities while keeping the core content relevant to NIDDK-supported organ systems and conditions. In practical terms, that means applications should center on HIV-related biology, behavior, or social mechanisms that influence diseases and processes such as diabetes and metabolism, digestive and liver diseases, kidney and urologic disorders, and related endocrine and nutritional pathways. The point is not to fund general HIV research, but rather HIV research that illuminates how infection, treatment, or associated determinants drive disease in NIDDK-relevant tissues and systems.

A major theme is understanding HIV comorbidities, coinfections, and complications (often shortened here as CCCs) that affect NIDDK mission areas. The opportunity calls for studies that explain unique pathophysiological mechanisms behind these CCCs in people with HIV, including how HIV infection and long-term antiretroviral therapy may alter immune function, inflammation, metabolism, organ-specific injury responses, tissue remodeling, or microbial and viral interactions in ways that worsen kidney, liver, gastrointestinal, metabolic, or endocrine outcomes. Projects can be framed around why certain complications occur, why they progress differently, or which biological pathways could be targeted to prevent or mitigate them.

Another highlighted area is HIV persistence and reservoirs in tissues relevant to NIDDK. The NOFO encourages work that interrogates biological mechanisms that allow HIV to persist in specific organ sites or cellular compartments connected to NIDDK interests, with the longer-term goal of informing strategies for durable viral suppression or eventual eradication. This can include studies that map where reservoirs reside, define the cellular and molecular environment that supports latency or persistence, and identify host or tissue factors that make certain reservoirs difficult to clear, especially when those reservoirs intersect with metabolic, renal, hepatic, or gastrointestinal biology.

The announcement also explicitly makes room for behavioral and social mechanisms, particularly social determinants of health, when they plausibly influence HIV-related CCCs or tissue reservoirs through identifiable pathways. That means projects can examine how structural, environmental, or social exposures (for example, food insecurity, housing instability, access to care, stigma, stress, or neighborhood-level factors) translate into measurable biological or clinical consequences in NIDDK-relevant conditions. The expectation is that proposals will go beyond simply documenting disparities and instead clarify mechanisms linking social conditions to disease processes, such as pathways involving chronic stress physiology, inflammation, adherence and treatment continuity, nutrition and metabolic effects, or care engagement patterns that ultimately affect organ outcomes or viral persistence.

From a funding mechanics standpoint, this is a discretionary NIH grant opportunity using the R21 activity, which is commonly used for exploratory and developmental projects. The activity category is listed broadly under health and related areas (CFDA 93.847). The NOFO is positioned as a pilot-study mechanism, so applicants should generally propose focused aims, strong innovation, and a plan to produce actionable preliminary data rather than an overextended multi-year definitive program. The original closing date listed for the opportunity is January 7, 2028, indicating a multi-year window during which receipt dates may occur, consistent with how many NIH program announcements operate.

Eligibility is broad and includes many types of U.S.-based organizations and governmental entities. Eligible applicants include state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; nonprofit organizations with or without 501(c)(3) status (excluding institutions of higher education in those categories); for-profit organizations (other than small businesses); small businesses; public housing authorities and Indian housing authorities; and federally recognized Native American tribal governments as well as tribal organizations that are not federally recognized governments. The NOFO also calls out additional eligible applicant types 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 (AANAPISIs), along with faith-based or community-based organizations and eligible federal agencies, reflecting an intent to encourage participation across a wide range of institutions.

At the same time, the policy on foreign involvement is specific. Non-domestic (non-U.S.) entities are not eligible to apply as the applicant organization, and non-domestic components of U.S. organizations are also not eligible to apply. However, foreign components are allowed as defined by the NIH Grants Policy Statement, meaning a U.S. applicant can include certain well-justified international elements within the project (for example, specific collaborations or resources abroad) if they meet NIH requirements and are appropriately described and approved.

Overall, PAR-25-068 is aimed at seeding new, mechanistically grounded lines of HIV research that intersect with diabetes, digestive and liver disease, kidney disease, metabolism, nutrition, and related NIDDK priorities. Competitive applications will typically make a clear case for (1) why the question matters to HIV pathogenesis and NIH HIV/AIDS priorities, (2) why it is specifically relevant to NIDDK mission organs and conditions, (3) what innovative mechanistic insight the pilot work will generate, and (4) how the results would position the field for stronger interventions, prevention strategies, or next-stage studies that address HIV-related comorbidities, tissue reservoirs, and the behavioral or social pathways that shape them.

• The National Institutes of Health in the food and nutrition, health sector is offering a public funding opportunity titled "Pilot Studies of Biological, Behavioral and Social Mechanisms Contributing to HIV Pathogenesis Within the Mission of NIDDK (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): 93.847.
• This funding opportunity was created on 2025-01-08.
• Applicants must submit their applications by 2028-01-07.
• 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 PAR 25 068

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