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

The U.S. Department of Health and Human Services, through the National Institutes of Health (NIH), has released a Notice of Funding Opportunity (NOFO) titled “Role of Defective Proviruses in HIV Persistence (R01 Clinical Trial Not Allowed)” under announcement number PAR-25-330. This funding opportunity involves multiple participating NIH institutes including the National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National Institute of Mental Health (NIMH). These institutes support research to advance understanding of HIV persistence, particularly the role of defective proviruses, which constitute the majority of proviruses in people living with HIV on antiretroviral therapy (ART). The purpose of this NOFO is to support research aimed at defining how defective HIV proviruses contribute to viral persistence, pathogenesis, immune response dysregulation, and challenges in the development of HIV cure strategies. Research is also encouraged to improve assays and methodologies by excluding defective proviruses from viral load and drug resistance testing to increase clinical accuracy. While clinical trials are not permitted under this opportunity, the research must involve human samples, including those collected from clinical trials or observational studies supported by other mechanisms. The scope includes basic research, methods development, and analysis of longitudinal blood and tissue samples. Use of SIV or SHIV primate models is excluded due to significant differences from HIV reservoirs. The NIH has identified specific areas of interest for each participating institute. NIAID is particularly interested in quantifying defective proviral reservoirs, understanding immune responses driven by defective epitopes, and developing clinical assays that can distinguish between defective and intact proviruses. NIDDK encourages studies in HIV reservoirs within organs such as the gut, kidney, liver, and adipose tissue, especially in individuals with relevant comorbidities. NICHD emphasizes research related to infants, children, and pregnant women living with HIV, including the impact of early ART initiation and longitudinal changes in reservoirs. NIMH supports studies on the neurological effects of defective HIV proviruses in the central nervous system and their impact on HIV cure strategies. Applicants may submit new, renewal, or resubmission applications under this program. Applications must adhere to NIH policies and the NIH Grants Policy Statement. Applications must use the ASSIST system, institutional system-to-system solutions, or Grants.gov Workspace for submission. Detailed data management and sharing plans are required, consistent with NIH policy. Applications that propose clinical trials, use SIV or SHIV models, or fail to analyze samples from people living with HIV will be considered non-responsive. Application budgets should not exceed $500,000 in direct costs per year, and the maximum project period is five years. The number of awards is dependent on NIH appropriations and the quality of submitted applications. The opportunity was first posted on December 9, 2024, with an application open date of April 7, 2025. The first AIDS-related application due date is May 7, 2025, followed by recurring submission dates on September 7, 2025, January 7, 2026, and continuing through January 7, 2028. The final expiration date of this NOFO is January 8, 2028. Applications are due by 5:00 PM local time of the applicant organization on the listed due dates. Peer review will occur in the months following each submission cycle, with advisory council reviews and potential earliest start dates following NIH’s standard review cycle. Evaluation will follow NIH peer review standards, focusing on the importance of the research, rigor and feasibility, and investigator expertise. Applications will be scored based on their potential to advance understanding of HIV persistence and cure strategies, methodological rigor, and the ability of investigators to access and analyze appropriate human samples. Budget justification and compliance with NIH policies will also be considered. Non-responsive applications will not be reviewed. Funding decisions will take into account scientific merit, program relevance, and the availability of funds. Applicants seeking assistance should contact the scientific and grants management staff for the relevant participating institute. Key scientific contacts include Leia Novak, PhD (NIAID), Jeymohan Joseph, PhD (NIMH), Eric Lorenzo, PhD (NICHD), and Khoa Dinhdang Nguyen, PharmD (NIDDK). Grants management contacts include Robert Kirker (NIAID), Rita Sisco (NIMH), Rehana A. Chowdhury (NICHD), and Sunshine Wilson (NIDDK). Technical assistance for application submission is available through the eRA Service Desk, NIH Grants Information office, and Grants.gov support. All applicants must ensure timely completion of required registrations in SAM, Grants.gov, and eRA Commons prior to submission.