NIAID, along with other participating NIH institutes and centers (ICs), invites research through the notice of funding opportunity (NOFO) Role of Defective Proviruses in HIV Persistence (R01, Clinical Trial Not Allowed) to characterize the role of defective HIV in blood and tissue sites in people living with HIV on antiretroviral therapy (ART).
During acute HIV infection, defective HIV proviruses can accumulate rapidly and constitute more than 90 percent of all proviruses in people living with HIV, regardless of the timing of ART initiation. Recent evidence suggests that the defective HIV reservoir does not decay over time, even after decades of ART administration, and expresses both viral RNAs and proteins in people living with HIV on ART with underexplored and unknown consequences. HIV protein expression from defective proviruses could interfere with intervention-mediated control of viral replication or rebound following a treatment interruption.
Research Objectives and Scope
Therefore, the goal of this NOFO is to resolve key questions regarding defective HIV reservoirs’ impact on 1) viral pathogenesis and antiviral immune responses on ART, 2) viral persistence, dynamics, and post-treatment control, or 3) responses to HIV cure strategies.
The NOFO also supports methods development and assay optimization to exclude defective proviruses from analyses to increase the accuracy and utility of crucial clinical assays.
The scope of your research may include basic research, methods development and validation, and the analysis of longitudinal blood and tissue samples from preclinical and clinical studies of people living with HIV and relevant animal models. While clinical trials are not allowed, NIAID does require the use of human samples and encourages the use of samples from clinical trials supported by other funding mechanisms or samples collected from observational studies.
NIAID-Specific Areas of Research Interest
NIAID is most interested in the following research activities:
- Quantify defective proviral transcription-/translation-competent reservoirs over time in people living with HIV on ART.
- Identify and define defective HIV protein epitopes that drive autologous anti-HIV immune responses and characterize the potential relevance of those responses to viral pathogenesis on ART, persistence, reservoir dynamics, post-treatment control, or responses to HIV cure strategies.
- Determine the contributions of defective proviral transcription-/translation-competent reservoirs to the detection of viral blips during ART or viral loads during analytical treatment interruptions.
- Analyze the effects of defective proviral Env expression on the impact of viral control mediated by therapeutic broadly neutralizing antibodies (bNAbs).
- Determine whether defective provirus integration sites play a role in host cell survival/proliferation or host gene expression.
- Analyze recombination events when defective provirus-harboring cells are superinfected with replication-competent HIV.
- Develop clinical assays, such as those used to quantify HIV viral loads, determine viral sensitivities to bNAbs, or to screen for known mutations that confer resistance to ART drugs, that exclude the detection of defective provirus.
Applications Not Responsive to This NOFO
NIAID considers research in the following areas to be nonresponsive and will not review them:
- Applications that propose clinical trials.
- Applications that include SIV or SHIV models.
- Applications that do not include analysis of clinical samples from people living with HIV.
- Applications focused primarily on intact HIV proviruses or that do not distinguish between defective and replication-competent proviruses.
- Applications that do not distinguish between transcription- and translation-competent vs. -incompetent defective proviruses.
Review Criteria Specific to This NOFO
Reviewers will consider criteria specific to this NOFO as part of the standard three factors to determine scientific merit and provide an overall impact score.
Within Factor 2: Rigor and Feasibility (Approach):
- Evaluate the validity, reproducibility, and sensitivity of methods proposed to distinguish between transcription- and translation-competent vs. incompetent defective proviruses.
- If applicable, assess the potential clinical utility and feasibility of implementation of methods/assays proposed to development/validation to exclude the detection of defective provirus from viral load measurements or during bNAb sensitivity/ART drug resistance screening.
Within Factor 3: Expertise and Resources (Investigator(s) and Environment):
- Evaluate whether the investigators have demonstrated access to relevant human samples.
Submission and Award Information
Application budgets are not expected to exceed $500K in direct costs per year and must reflect the actual needs of the proposed project. The scope of the proposed project should be determined by the project period, and the maximum project period is 5 years.
Application deadlines follow NIH’s standard AIDS due dates, i.e., May 7, September 7, and January 7 by 5 p.m. local time of the applicant organization, through January 7, 2028.
Contact Information
Direct your inquiries to NIAID’s scientific/research contact, Dr. Leia Novak, at leia.novak@nih.gov or 301-761-7825.