The National Institute of Allergy and Infectious Diseases (NIAID), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute of Mental Health (NIMH), has issued the *Role of Defective Proviruses in HIV Persistence (R01 Clinical Trial Not Allowed)* funding opportunity (PAR-25-330). This funding supports research to understand how defective HIV proviruses contribute to HIV persistence, pathogenesis, and challenges to HIV cure strategies during antiretroviral therapy (ART). Defective proviruses represent the majority of HIV reservoirs, and their role in immune activation, viral dynamics, and therapeutic responses remains underexplored.

The focus of this opportunity is to define the impact of defective HIV proviruses on HIV pathogenesis, immune responses, and reservoir dynamics. It also encourages the development of methods to exclude defective proviruses from key clinical assays to improve their accuracy, such as viral load measurements, bNAb sensitivity tests, and ART resistance screening. Research can involve basic science, technical assay development, and analysis of longitudinal blood and tissue samples from clinical studies of people living with HIV on ART. Projects may include identifying transcription- and translation-competent defective proviruses, their role in immune responses, or their effects on HIV cure interventions.

Eligible organizations include higher education institutions, nonprofits, for-profit organizations, local and tribal governments, and foreign institutions. Applications must include the analysis of clinical samples from individuals living with HIV and exclude the use of SIV or SHIV animal models. Studies primarily focusing on intact HIV proviruses, or those unable to distinguish transcription- or translation-competent defective proviruses, will be considered non-responsive.

NIDDK encourages projects that study HIV reservoirs in anatomical sites relevant to its mission, such as the gut, liver, kidney, genital tract, and adipose tissue, particularly in individuals with co-infections or comorbidities. NICHD supports research on defective proviruses in children, pregnant individuals, and early ART-treated infants. NIMH focuses on the role of defective proviruses in the central nervous system, including their impact on neuropathogenesis and cure strategies targeting the brain.

The award provides up to $500,000 in direct costs per year for a maximum project period of five years. Applications will be evaluated based on their significance, innovation, rigor, feasibility, and the investigators' expertise and access to clinical samples. Key deadlines include May 7, 2025, September 7, 2025, and subsequent standard AIDS application due dates through January 7, 2028. Applicants must adhere to NIH submission guidelines, including registrations in SAM.gov, eRA Commons, and Grants.gov.

For inquiries, applicants are encouraged to contact NIH program officials listed in the announcement. Detailed submission instructions and eligibility requirements are available in the funding notice on Grants.gov.