Despite generalized conceptual understanding of HIV persistence across a population of cells, there is a fundamental lack of understanding and differentiation of the molecular details at the single-cell level. Traditional bulk cell population assays obscure critical insights on the heterogeneity and spatiotemporal dynamics of the HIV reservoir. Given that the latent HIV reservoir is inherently heterogeneous, dissection of single-cell characteristics is required to comprehensively define parameters for HIV latency, reactivation, and elimination.
Purpose and Research Objective
The overall goal of this FOA is to foster basic science research to address outstanding questions in HIV latency and persistence. The scientific objective is to harness innovative single-cell and multi-omics platforms to investigate mechanisms of HIV persistence at the single-cell level with greater precision and higher resolution than has been achieved previously using traditional techniques. Emphasis will be on multi-omics or parallel approaches integrating multiple cutting-edge single-cell analysis technologies. These combinatorial approaches will enable highly innovative basic HIV research to characterize pathways, factors, and biomarkers involved in HIV persistence, latency, latency reversal, killing of reservoir cells, viral recrudescence or rebound, and control of viremia.
The objectives are to facilitate interdisciplinary research among bioinformaticians, bioengineers, HIV basic scientists, and HIV clinicians with access to relevant clinical specimens. It is anticipated that these collaborations will generate novel single-cell multi-omic approaches to address outstanding gaps in understanding HIV persistence. Curing HIV infection may require innovative strategies to identify and eliminate reservoir cells with single-cell precision. Single-cell multi-omic studies will reveal comprehensive molecular details of the HIV reservoir, including proviral integration site selection, epigenomics, viral transcription, protein expression, and/or clonal proliferation at single-cell resolution. These innovative combinatorial single-cell studies will illuminate novel insights into HIV persistence and ultimately inform eradication efforts.
Specific Areas of Research Interest
The overarching research objectives are to support highly innovative combinatorial single-cell analysis approaches to investigate and characterize HIV latency and persistence. Combinatorial single-cell analyses in parallel may include state-of-the-art single-cell genomics, epigenomics, transcriptomics, epitranscriptomics, proteomics, and/or metabolomics to characterize persistently infected cells derived from antiretroviral therapy (ART)-suppressed individuals, animal models, lymphoid and other HIV-susceptible tissues, and primary cell models. Studies to be supported may be both hypothesis-driven and/or descriptive in nature toward addressing the research goals. Research examples of interest include, but are not limited to:
- Identify and characterize novel pathways and factors involved in HIV persistence, latency, latency reversal, cell killing, viral rebound, and control of viremia
- Characterize defective proviruses (transcriptionally silent vs. RNA positive vs. translation competent) and their roles in inflammation, HIV persistence, and impact on eradication strategies
- Discover and validate DNA, RNA and/or protein signatures or biomarkers of latency at the single-cell level
- Investigate the single-cell determinants of cytotoxic T lymphocyte (CTL) and/or natural killer (NK) cell killing and elimination of reservoir cells
- Quantify the distribution and diversity of clonal expansion throughout the host
- Characterize individual cellular responses to curative interventions
- Develop an “atlas” of the persistent HIV reservoir in various hosts and tissues
NIMH Interest Statement: The National Institute of Mental Health is specifically interested in multi-omics or multiplex approaches integrating cutting-edge single-cell analysis technologies to study mechanisms of HIV latency and persistence in central nervous system (CNS)/cerebrospinal fluid (CSF)-derived cells.
Applications proposing the following will be considered non-responsive and will not be reviewed:
- Traditional systems biology studies exclusively using bulk cell populations
- Studies exclusively using cell line models or primary cell models without subsequent extension to cells derived from ART-suppressed individuals, animal models, lymphoid or other HIV-susceptible tissues
- Studies not combining multiple single-cell analyses (e.g., solely performing single-cell RNA-seq)
Applicants are highly encouraged to contact the program officials listed under Scientific/Research Contact(s) listed in Section VII to discuss their applications prior to submission to ensure research topics could be supported under this FOA.
Deadline: February 13, 2019 (letters of intent); March 13, 2019 (full proposals)
URL: https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-18-053.html
Filed Under: Funding Opportunities