Concepts represent early planning stages for program announcements, requests for applications, or solicitations for Council's input. If NIAID publishes an initiative from one of these concepts, we link to it below. To find initiatives, go to Find a Funding Opportunity.
NB: Council approval does not guarantee that a concept will become an initiative.
Table of Contents
- Detection of HIV for Self-Testing
- Dysregulation of Immune Cell Regulatory Pathways by Mtb in the Context of HIV Infection
Program Announcement With Special Receipt, Referral, and/or Review Considerations—proposed FY 2018 initiative
Contact: Diane Lawrence
Objective: The objective is to support interdisciplinary research and development of innovative diagnostic technologies designed to facilitate increased in-home HIV testing. The proposed research should define milestones that demonstrate sensitivity, specificity, and feasibility to address the need for 1) increased awareness of infection status, especially during the initial two to eight weeks of infection when viral load and risk of transmission are greatest and/or 2) enhanced monitoring of viral suppression in HIV-infected individuals on antiretroviral therapy (ART).
Description: This initiative will support basic and translational research collaborations to develop and optimize simple qualitative assays to directly detect HIV (RNA, DNA, or protein) or other biomarkers that reliably correlate with viral load. The assays should allow sensitive detection of HIV at the earliest possible time post-infection or after loss of viral suppression by ART, ideally corresponding to a plasma viral load of 200 to 1,000 copies/ml. For monitoring viral suppression, the assay should appropriately consider the need to prevent detection of cell-associated HIV DNA and RNA. Developing such technology will require collaboration among experts in the fields of virology and biotechnology (e.g., microfluidics, bioengineering, synthetic biology, nanotechnology, manufacturing).
Applications will describe a five-year project in two phases. The initial research phase would define the intended goal(s) for detection and outline milestone-driven proof-of-concept studies. The later R33 phase would involve expanded assay development and optimization, determination of performance specifications, and validation with human samples. Successful projects would inform later product development efforts; ultimately, the assays should be simple to use with no training required, allow convenient sampling of biospecimens, be easy to repeat for regular testing, provide a rapid readout, and be designed to be relatively inexpensive and easy to package and distribute.
Request for Applications—proposed FY 2018 initiative
Contact: Daniel Frank
Objective: The objectives of this initiative are to:
- Support exploratory preclinical research to identify Mycobacterium tuberculosis (Mtb)-mediated changes in key cell regulatory mechanisms of immune responses as potential targets of host-directed therapy in the context of HIV infection. Applications will propose a specific hypothesis and approach(es) to identify the specific molecular basis of an identified target.
- Evaluate (using in vitro, ex vivo, and/or animal models) strategies for reversing the disrupted expression/activity of identified target immune cell regulatory molecules including, but not limited to, available drugs for re-purposing to treat TB and TB/HIV infection/disease and potentiating vaccine effectiveness.
Description: This initiative will support exploratory preclinical research to identify and characterize changes in key regulatory cell signaling pathways, epigenetic changes, or other relevant gene expression control mechanisms of human immune cells caused by Mtb infection with and without HIV co-infection. Multidisciplinary research teams involving investigators with experience in the study of diseases caused by alterations in molecular regulation (e.g., aging, cancer, neurodegenerative diseases), fundamental cell regulatory pathways, relevant immune cell functions and interactions, and Mtb pathogenesis are strongly encouraged.
Applications will describe a five-year project in two phases. Phase 1 (R61, two years) will focus on identifying changes in TB and TB/HIV in infected macrophages/dendritic cells, and as appropriate, subsequent regulatory changes in Mtb- and/or HIV-reactive uninfected innate and adaptive immune cells. Specific molecular immune cell regulatory mechanism changes induced in these cells will be delineated as potential targets for host-directed therapeutic interventions.
In Phase 1, target molecules will be identified and characterized to inform efforts to test therapeutic interventions for the affected immune response control pathways. Potential target candidates may include:
- Specific immune cell regulatory signaling pathway molecules altered in expression, function, and/or activity by Mtb infection
- Epigenetic changes induced directly by Mtb or indirectly by Mtb through induced alterations in cell regulatory signaling pathways, and subsequent changes in immune cell pathway molecules caused by these epigenetic modifications
- Alterations in molecular regulatory control of:
- Immune cell co-receptor/ligand checkpoints (such as PD-1 or CTLA-4)
- Immunometabolic checkpoints that help determine immune cell differentiation and function
- Antibody-mediated modulation of innate cell immune signaling and function
- Suppressor cell population (Tregs, MDSCs, M2 polarized macrophages) induction and activity
- Changes in immune cell pathway signaling molecules and effector functions that may be caused by subsequent modifications of these mechanisms
Phase 2 of the application will describe a strategy to modulate the target to confirm its immunopathogenic relevance and to begin therapeutic agent identification/evaluation in an appropriate model system. Strategies may include using small molecules, biologics, miRNA, or other methods of restoring or enhancing host immune regulation and to evaluate changes in bacterial load, immune cell bactericidal activity, inflammatory control, and prevention of tissue damage. Ideal targets will show potential for further investigation in clinical studies as host-directed therapy against Mtb in the context of HIV co-infection.
Repurposing of small molecules already in use for other therapeutic interventions is highly encouraged.
When Phase 1 ends, applicants will submit a transition application that NIH staff will evaluate for completion of Phase 1 milestones, program priorities, and funding availability. It is expected that half of Phase 1 projects will continue onto Phase 2.
Research approaches making innovative use of novel research tools, particularly at the single-cell level, to elucidate molecular alterations in fundamental immune cell regulatory pathways and epigenetic changes caused by TB and TB/HIV are encouraged.
Phase 1 and 2 applications will be considered nonresponsive if they:
- Intend to identify or modulate cytokines/interleukins, chemokines, interferons, or eicosanoids as targets
- Do not include examining targets in the context of Mtb and TB/HIV infection
- Propose broad drug screening efforts