Mechanistic Evaluation of Therapeutic Targets derived from Treatable Traits to Improve CNS Outcomes in People with HIV (R21/R33 Clinical Trial Not Allowed) | RFA MH 27 125

Frequently Asked Questions (FAQs)

What is the title and funding opportunity number for this NIH grant?

The funding opportunity is titled "Mechanistic Evaluation of Therapeutic Targets derived from Treatable Traits to Improve CNS Outcomes in People with HIV (R21/R33 Clinical Trial Not Allowed)" and the Funding Opportunity Number is RFA-MH-27-125.

What is the main goal of this funding opportunity?

The main goal is to move the field beyond describing HIV-related central nervous system (CNS) problems and toward identifying specific, modifiable biological mechanisms that can be targeted with new therapies. The NIH is looking for projects that generate experimentally supported rationales for therapeutic targets and intervention concepts relevant to CNS outcomes in people with HIV.

What kinds of HIV-related CNS issues is this opportunity trying to address?

This NOFO is motivated by the fact that, even with effective antiretroviral therapy, many people with HIV continue to experience neurological and neuropsychiatric complications. It recognizes these outcomes can be multifactorial, vary from person to person, and involve overlapping biological pathways rather than a single uniform cause.

What does the NOFO mean by a "treatable traits" approach?

The "treatable traits" framing means applicants are expected to focus on measurable traits or phenotypes that reflect underlying biological processes and that could plausibly be modified to improve CNS outcomes. Rather than treating HIV-associated CNS dysfunction as one monolithic condition, the NOFO emphasizes identifying traits that map to mechanisms and can guide more targeted therapeutic thinking.

How does this opportunity expect researchers to handle patient heterogeneity?

The NOFO explicitly highlights heterogeneity as a central challenge and encourages projects that disentangle it by grouping or stratifying patients into phenotypes that share convergent pathophysiological features (shared mechanisms). The idea is that identifying mechanistically coherent subgroups can make it more feasible to discover actionable targets and propose interventions matched to the biology driving a given phenotype.

What does "convergent pathophysiological features" mean in this context?

In this NOFO, convergent pathophysiological features refer to shared underlying mechanisms that may cut across conventional diagnostic labels. The NOFO provides examples of mechanistic patterns such as neuroinflammation, vascular dysfunction, synaptic injury, glial activation, persistent viral effects, immune dysregulation, metabolic contributors, and other overlapping mechanistic pathways.

What is the R21/R33 phased award structure?

This opportunity uses a phased R21/R33 structure designed to support a developmental-to-advanced research pipeline within a single application. The R21 phase supports early, high-impact work that establishes the foundation, and the R33 phase supports more robust mechanistic discovery and validation work that builds on successful R21 progress.

What types of activities are expected in the R21 phase?

Based on the description provided, the R21 phase is generally oriented toward early work such as defining or refining phenotypes, assembling evidence for mechanistic convergence, generating preliminary mechanistic hypotheses, and establishing feasibility of the experimental approach.

What types of activities are expected in the R33 phase?

The R33 phase is positioned for more rigorous mechanistic discovery and validation. This includes testing proposed molecular mechanisms more robustly and experimentally evaluating therapeutic targets, building from the phenotype definition and feasibility work established earlier.

Is experimental validation required, or are descriptive/observational studies sufficient?

The NOFO stresses experimental validation rather than purely observational or descriptive work. Across both phases, the emphasis is on moving from phenotype definition toward mechanism, and from mechanism toward experimentally supported therapeutic targets.

What kinds of model systems does the NOFO emphasize?

The NOFO stresses the use of innovative in vitro and in vivo model systems to support mechanistic testing and validation of therapeutic targets.

Are clinical trials allowed under this opportunity?

No. This NOFO is designated "Clinical Trial Not Allowed." That means the funded work should not be designed as a clinical trial that prospectively assigns human participants to an intervention to evaluate effects on health-related outcomes.

If clinical trials are not allowed, can projects still use human participants, samples, or data?

Yes, the NOFO indicates the program can include preclinical, translational, and mechanistic human research, including the use of human samples or data for phenotype and mechanistic inference, as long as the study is not structured as an interventional clinical trial.

What is the expected overall deliverable or end product of funded projects?

The overall deliverable NIH is aiming for is a stronger, experimentally supported rationale for specific therapeutic targets and intervention strategies that can later be tested using appropriate clinical trial mechanisms (outside the scope of this NOFO).

What NIH institute or general domain is this opportunity associated with?

It is an NIH funding opportunity in the health research category, focused on improving CNS outcomes in people with HIV through mechanistic evaluation and therapeutic target development.

What are the CFDA numbers associated with this opportunity?

The opportunity is associated with CFDA numbers 93.242, 93.279, and 93.853.

Who is eligible to apply (in general terms)?

The opportunity is open to a broad range of eligible applicant organizations, including state, county, and local governments; public and private institutions of higher education; federally recognized tribal governments and other eligible tribal entities; public housing authorities/Indian housing authorities; nonprofit organizations (including 501(c)(3) and non-501(c)(3) nonprofits); and for-profit organizations (including small businesses and other for-profit entities, excluding non-eligible categories as specified in the notice).

Are foreign organizations eligible to apply?

No. Non-U.S. entities (foreign organizations) are not eligible to apply.

Can a U.S. organization include a non-U.S. component or site as part of the project?

No. Non-U.S. components of U.S. organizations are not eligible, and foreign components (as defined by the NIH Grants Policy Statement) are not allowed. The work supported under this NOFO must be conducted without foreign components.

How should applicants handle collaborations given the foreign component restrictions?

Applicants should plan collaborations and project sites to ensure there are no foreign components. For nuanced questions (such as what qualifies as a foreign component), the NOFO directs applicants to consult Section III (Eligibility Information) and align with NIH policy definitions.

What is the application due date listed in the opportunity summary provided?

The original closing date provided is October 28, 2027.

What is the central scientific strategy encouraged by this NOFO?

The strategy is a mechanism-building and target-validation pipeline: define clinically meaningful and biologically coherent phenotypes (treatable traits), identify modifiable mechanisms that appear to drive them, and experimentally validate therapeutic targets using modern model systems to better ground future intervention development in causality and patient-relevant biology.