Role of Defective Proviruses in HIV Persistence (R01 Clinical Trial Not Allowed)

The National Institutes of Health (NIH), under the U.S. Department of Health and Human Services, released the funding opportunity titled "Role of Defective Proviruses in HIV Persistence (R01 Clinical Trial Not Allowed)," designated by opportunity number PAR-25-330. This initiative was managed in collaboration with several NIH components, including the National Institute of Allergy and Infectious Diseases (NIAID), 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). The purpose of this notice of funding opportunity (NOFO) is to support innovative and high-impact research that investigates the role of defective HIV proviruses in viral persistence, pathogenesis, and how they may impede or interfere with the accuracy of assays and the success of HIV cure strategies during antiretroviral therapy (ART). Defective HIV proviruses are known to dominate the proviral landscape in individuals with HIV on ART, constituting over 90% of all proviruses regardless of treatment timing. These proviruses, despite being non-replicative, express viral RNAs and proteins that could contribute to immune activation and comorbidities, impact immune responses, or serve as decoy epitopes, thus impairing the immune system’s capacity to manage intact viruses. This NOFO aims to stimulate research to explore these mechanisms, understand the persistence of such proviruses over time, and develop improved clinical assays that accurately exclude defective proviruses to prevent misleading results in HIV diagnostic and monitoring tests. This program explicitly excludes clinical trials but strongly encourages the use of human samples, particularly from people living with HIV. Research utilizing SIV or SHIV models is deemed non-responsive due to differences in provirus composition from human HIV models. Projects may include comparative analyses across different HIV subtypes, longitudinal studies in specific populations like infants, children, and pregnant women, and exploration of proviral expression in diverse anatomical sites such as the gut, liver, and brain. NIDDK, NICHD, and NIMH have delineated particular areas of interest aligned with their respective missions, including studying comorbidities, developmental impacts, and neuropathogenesis related to defective proviruses. The allowable budget per application is up to $500,000 in direct costs per year, with a maximum project period of five years. Matching or cost-sharing is not required. Applications could be submitted beginning April 7, 2025, with recurring AIDS-specific submission cycles every four months (May, September, and January), continuing until the early expiration date of February 19, 2026, as noted in NOT-AI-26-007. Although the notice has expired, in limited cases late submissions may still be accepted in line with NIH’s continuous submission policies. Eligible applicants span a wide spectrum, including higher education institutions, for-profit entities, local and state governments, nonprofits, tribal entities, and foreign organizations. International institutions and foreign components of U.S. institutions are permitted to apply. Submission must be made electronically via ASSIST, Grants.gov Workspace, or an institutional system-to-system portal. Applicants are expected to conform to NIH’s extensive application guide, including the development of a data management and sharing plan, justification of sample access, and clear delineation of methods to distinguish between transcriptionally and translationally competent and incompetent proviruses. The evaluation criteria encompass significance, innovation, and approach, with a specific focus on the reproducibility and relevance of methods, the potential impact on HIV cure strategies, and the feasibility of translating the findings into improved clinical applications. Peer review will be conducted through NIH’s standard review groups, with advisory council input determining final funding decisions. Key contacts for scientific, peer review, and financial queries are provided across the participating NIH institutes.

Ensure clarity in differentiating provirus types and access to human samples is well-documented.