Through Tailoring HIV Curative Strategies to the Participant (UM1, Clinical Trial Not Allowed), NIAID supports the development of clinical research platforms to enable proof-of-concept studies to demonstrate that combinations of interventions specifically tailored to target a participant’s unique, intact, rebound-competent HIV reservoir, and that also complement their distinct immunologic profile, have the potential to be curative for HIV.
Although people living with HIV depend on daily antiretroviral therapy (ART) to maintain viral suppression, ART is not curative due to the virus’s ability to enter a latent state where it is impervious to immune-mediated clearance. HIV curative research is one of NIAID’s highest research priorities since lifelong ART presents challenges for people living with HIV at both the individual and societal levels.
Research Objectives and Scope
We encourage applicants to assemble highly collaborative, multidisciplinary teams with expertise in virology, immunology, single-cell analysis, bioinformatics, and clinical research. Your team will develop a practical clinical research platform for rapidly and efficiently profiling participants’ intact, rebound-competent HIV reservoirs and their immunologic profiles to provide relevant information needed to design a tailored combination of curative interventions for each participant.
HIV curative approaches must specifically target each participant’s virologic and immunologic profile, with a goal of significant reduction or eradication of the rebound-competent HIV reservoir or the induction of durable post-treatment control of HIV viral rebound. Examples of participant profiling include in-depth characterization of the landscape of intact and defective proviruses, host major histocompatibility complex (MHC) alleles, CD4+/CD8+ T cell receptor repertoires, autologous neutralizing antibody (aNAb) specificities and titers, and proviral sensitivity to broadly neutralizing antibodies (bNAbs).
The scope of this notice of funding opportunity (NOFO) includes basic and preclinical research as well as methods development and validation for optimal, rapid screening of potential participants in future clinical trials testing tailored HIV curative strategies.
Applicants should include combinatorial HIV curative strategies with at least two tailored immunologic-based approaches, such as the examples below:
Selecting peptides exclusive to intact, rebound-competent proviruses that are predicted for presentation by a participant’s MHC Class I/II molecules and prioritized for resistance to immune escape for:
- Inclusion in a T cell-targeted therapeutic vaccine modality.
- Designing engineered T cell receptors for development of an autologous or heterologous effector cell product.
- Expanding specific immune cells ex vivo for reinfusion.
Sequencing a participant’s intact, rebound-competent proviral Envs for:
- Tailoring appropriate combinations of bNAbs for passive delivery.
- Developing CAR T or CAR NK cell products.
- Engineering antibody-based therapeutics such as dual affinity retargeting antibodies (DARTs) or bi- and tri-specific killer cell engager antibodies (BiKEs and TriKEs).
- Selecting aNAbs targeting immune escape-resistant epitopes and further optimizing or expanding aNAb-expressing B cells ex vivo for reinfusion.
Applicants should also include examples of tailored approaches for reactivating latent, rebound-competent HIV including:
- Determining antigen specificalities of CD4+ T cells harboring intact, rebound-competent provirus to design strategies to specifically activate those infected cells.
- Analyzing the intact, rebound-competent proviral promoter sequences and epigenetic landscape to tailor combinations of appropriate latency reversing agents.
- Characterizing the phenotypes and gene expression profiles of CD4+ T cells harboring intact, rebound-competent proviruses to identify specific ways to target latency reversing agents to those cells.
- Testing intact, rebound-competent provirus-infected T cell clones for viral reactivation with combinations of latency reversing agents.
There are several criteria which, if included, will cause NIAID to deem your application nonresponsive and not review it. Your application must not:
- Propose clinical trials.
- Include viral or host gene editing approaches, such as CCR5 co-receptor editing or HIV LTR editing.
- Fail to include at least two tailored immunologic-based approaches.
- Focus primarily on SIV or SHIV.
- Fail to include analysis of clinical samples from people living with HIV.
- Limit testing of interventions to HIV-infected cell lines.
Award and Application Information
NIAID will fund two or three awards. Application budgets are not expected to exceed $2 million in annual direct costs and must reflect the actual needs of the proposed project. The total project period must be 5 years.
Applications are due on July 30, 2024, by 5:00 p.m. local time of the applicant organization.
Contact Information
Send related inquiries to NIAID’s scientific/research contact, Dr. Leia Novak, at Leia.novak@nih.gov or 301-761-7825. Send peer review related inquiries to Dr. Kristina Wickham at Kristina.wickham@nih.gov or 301-761-5390.