Key Dates

Related Announcements

PAR-23-297 - Opportunities for HIV Cure Strategies at the Time of ART Initiation (R01 Clinical Trial Not Allowed)

PAR-23-296 - Opportunities for HIV Cure Strategies at the Time of ART Initiation (R21 Clinical Trial Not Allowed).

NOT-AI-23-072 - Notice of Early Expiration of "Notice of Special Interest (NOSI): Opportunities for HIV Cure Interventions at the Time of ART Initiation", NOT-AI-22-072.

NOT-AI-22-056 - Notice of Special Interest (NOSI): Opportunities for HIV Cure Interventions at the Time of ART Initiation

NOT-AI-22-066- Notice of Early Expiration of "Notice of Special Interest (NOSI): Opportunities for HIV Cure Interventions at the Time of ART Initiation", NOT-AI-22-056

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-21-235 - NIMH Exploratory/Developmental Research Grant (R21 Clinical Trial Not Allowed)

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Mental Health (NIMH)

Purpose

This Notice of Special Interest (NOSI) serves to identify new opportunities for cure strategies during active HIV infection at or near the start of antiretroviral therapy (ART) or as a potential replacement for conventional ART, with the ultimate goal of achieving a sustained ART-free HIV remission.

Background

The initiation of ART within the first few weeks of HIV infection has been associated with the development of a smaller latent reservoir, reduced viral diversity, preservation of innate as well as T and B cell immune responses, and higher rates of post treatment control. Additional interventions, in combination with the start of ART, may potentially accelerate viral decay, limit reservoir seeding, and induce a vaccinal effect that, in combination, may induce HIV remission. Currently, HIV cure approaches are focused almost exclusively on interventions administered during complete viral suppression on ART. Recent scientific evidence suggests that much of the reservoir is stabilized at the time of ART initiation. It is thought that ART alters the host environment in a way that promotes the formation of most of the long-lived latent HIV reservoir. Therefore, there is an opportunity to explore novel strategies designed to limit the establishment of the HIV reservoir around the time of ART initiation. In more translational studies, some early interventions using broadly neutralizing antibodies in the absence of ART have led to sustained remission in non-human primates (NHP). Therefore, opportunities also exist to intervene before complete ART-mediated viral suppression, when HIV antigen is stimulating the immune response, to improve clinical outcomes toward an HIV cure.

Research Objectives

The scientific objective of this NOSI is to support projects to explore HIV cure approaches administered during active HIV/SHIV/SIV infection, prior to or around the time of ART initiation, before viral loads are completely suppressed, or after an analytical treatment interruption to potentially enhance the ongoing immune response and prevent additional reservoir seeding. A better understanding of the decay dynamics of various virus-infected cell subsets following ART initiation is also needed. Therefore, longitudinal studies of the viral reservoir early in active infection and immediately after ART initiation, will be supported to inform the development of new cure strategies. Additionally, basic research into the unique mechanisms that contribute to intervention-mediated viral control and reductions in reservoir size will be important. The curative approaches studied should be experimental, innovative, and not yet approved by the FDA or a foreign regulatory agency for an HIV indication.

Under this NOSI, clinical trials are not allowed, but the use of samples from clinical trials supported by other funding mechanisms is encouraged. Studies in animal models, using HIV, SIV, or SHIV, are included in the scope. Therapeutic strategies should be evaluated in an in vitro cell-based model prior to in vivo studies.

Examples of basic research activities include but are not limited to:

• Research to detect, quantify, and characterize HIV/SIV reservoir seeding in different cell types and tissues at various time points near ART initiation or during therapeutic intervention prior to ART initiation. Suggested topics could include comparing different HIV subtypes, acute versus chronic infection, humans versus animal models, and different ages and sex of individuals.
• Analyzing the HIV reservoir dynamics, decay rates of various cell types, clonal proliferation, proportion of intact versus defective HIV/SIV, distribution of active versus latent reservoirs, and reactivation potential of latent HIV/SIV at or near the time of ART initiation or during therapeutic intervention prior to ART initiation.
• Comparing reservoir or immunologic changes in response to strategies delivered at different time points or in place of conventional ART.

Applicants may use in vivo animal models and/or existing ex vivo human clinical samples.

Examples of targeted interventions activities but are not limited to:

• Identifying experimental cure/remission approaches in cell models ex vivo or animal models in vivo prior to or at the initiation of ART that contribute to a reduction in reservoir size, an increased decay rate of the reservoir, or post-treatment control of viral rebound. Successful strategies could also be later employed during an analytical treatment interruption.
• Identifying short-term strategies in pre-clinical models, instead of or in combination with ART, that could differ from life-long ART in enabling durable control of rebound with one-time or very intermittent use.

Examples of strategies include but are not limited to:

• Strategies to eliminate HIV-infected cells
• Inhibiting latency establishment before/at ART start
• Preventing clonal expansion of reservoir cells
• Preventing wide HIV dissemination and approaches to block HIV trafficking
• Limiting reservoir seeding in sanctuary sites (e.g., B cell follicles)
• Optimizing and boosting the anti-HIV immune response

For applications proposing the use of novel interventions, the participation of an intellectually contributing private sector/industry partner as a significant collaborator in the application is strongly encouraged.

Team science, especially the inclusion of early-stage investigators, and collaborations with groups collecting clinical samples from cure trials are also encouraged.

NIMH areas of programmatic interest include but are not limited to:

• Both basic research activities and targeted interventions to explore HIV cure approaches administered during active HIV/SHIV/SIV infection, prior to or around the time of ART initiation, before viral loads are completely suppressed with a focus on the brain and central nervous system derived cells (macrophages, microglia, astrocytes).

• Studies that use communication science in relation to cure approaches at the time of treatment initiation to 1) optimize HIV cure research literacy (e.g., HIV cure; viral eradication; sustained ART-free HIV remission, etc.) for improved engagement and understanding, and 2) to optimize informed consent processes, understanding of the risks and/or benefits to HIV cure research participation, and decision-making.

NICHD areas of programmatic interest include but are not limited to:

• Research to characterize, quantify and compare (phylogeny) the plasma virus RNA of newborns and children with both the myeloid and lymphoid cell proviral DNA, at or near the time of ART start, or during therapeutic intervention prior to ART initiation.

• Research to characterize changes in the antibody response to HIV in newborns and children at various time points, near the time of ART start,or during therapeutic intervention prior to ART initiation.

Applications will be considered non-responsive to this NOSI if the applications:

• Propose interventions that begin more than one month after initiation of ART.
• Represent ART intensification strategies alone without inclusion of non-ART based interventions.
• Propose to utilize FDA-approved drugs as curative interventions without a rationale for disrupting an HIV-associated pathway and without a mechanistic approach.
• Propose clinical trials.

Application and Submission Information

This Notice applies to due dates on or after January 7, 2023 and subsequent receipt dates through September 7, 2025.

Applicants must select the IC and associated FOA to use for submission of an application in response to the NOSI. The selection must align with the IC requirements listed in order to be considered responsive to that FOA. Non-responsive applications will be withdrawn from consideration for this initiative. In addition, applicants using NIH Parent announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those FOAs are acceptable and based on usual application-IC assignment practices.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this Notice.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-AI-22-072 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Scientific/Research Contact(s)

Brigitte Sanders, DVM, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3209
Email: sandersbe@niaid.nih.gov

Eric Lorenzo, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-443-4993
Email: eric.lorenzo@nih.gov

Jeymohan Joseph, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 240-627-3869
Email: jjeymoha@mail.nih.gov