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

Background
The National Institutes of Health (NIH), specifically the National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and National Institute of Neurological Disorders and Stroke (NINDS), are issuing this Notice of Funding Opportunity (NOFO) to identify modifiable mechanisms and therapeutic targets to address central nervous system (CNS) complications associated with human immunodeficiency virus (HIV).

The initiative aims to advance therapeutic target and intervention discovery to tackle the multifactorial and heterogeneous nature of HIV-associated CNS dysfunction.

Grant Details
This NOFO supports a phased research approach that includes:
1. Identification of patient phenotypes characterized by convergent pathophysiological features.
2. Discovery and experimental validation of molecular mechanisms using innovative in-vitro and in-vivo models.

The R21 phase will provide up to 2 years of support for initial developmental activities, while the R33 phase will allow for an additional 3 years for expanded activities. Proposed projects must include both phases, with milestone-driven developmental activities in R21 leading to expanded activities in R33. Key tasks include:
- Identifying or leveraging previously defined subgroups of people with HIV experiencing CNS complications.
- Prototyping and testing phenotype-derived platforms such as patient-derived organoids.
- Evaluating hypothesis-based mechanisms using in vitro platforms followed by profiling candidate interventions.
- Validating mechanisms across complementary models in the R33 phase.

Eligibility Requirements
Eligible applicants include higher education institutions, nonprofits, for-profit organizations, local governments, state governments, tribal governments, and various other entities as specified in the eligibility section. Non-domestic entities are not eligible to apply.

Period of Performance
The total project period may not exceed 5 years, consisting of a maximum of 2 years for the R21 phase and up to 3 years for the R33 phase.

Grant Value
NIMH intends to commit a total of $2.5 million in FY27 and FY28 to fund up to 2-3 awards. NINDS intends to commit $1 million in fiscal years 2027 and 2028 for one award, while NIDA plans to commit $1 million for up to 1-2 awards during the same period. In the R21 phase, direct costs may not exceed $275,000 over two years, with no more than $200,000 in any single year; in the R33 phase, direct costs may not exceed $650,000 per year.