Purpose

The overarching goal of this notice of funding opportunity (NOFO) is to support research on neuroimmune axes and their impacts on the etiology and pathogenesis of HIV and substance use disorder (SUD) comorbidity. The initiative will support research on targeting the causal biology and the bidirectional molecular pathways orchestrating communication between the brain and the immune systems, with an emphasis on elucidating mechanisms and identifying therapeutic targets.The initiative will also support research towards the discovery of novel chemical probes/tools for characterizing neuroimmune interactions and modulating neuroimmune communications. The knowledge acquired should assist in identifying therapeutic interventions for mitigating HIV-associated neurological manifestations including neurodegeneration, cognitive impairment, neuroinflammation, and pain, which are exacerbated by substance use.

Background

Misused substances alter immune and neuronal cell function and are known to impact HIV neuropathogenesis and affect adherence to antiretroviral therapy. Substances as single entities, or combinations (polysubstance), add a level of complexity to cellular trafficking and various pro-inflammatory and/or toxic mediator release events. Depending on the substance/s, their misuse may exacerbate HIV disease progression. SUD as a comorbidity has been shown to modulate HIV transcription. The neural and immune responses that accompany HIV infection along with substance use can include unique neuro-inflammatory processes followed by changes in neuronal activity and function at both the single cell and circuit levels. These phenomena possibly occur via diverse mechanisms; some that could be modeled within the CNS and its barriers, others within specialized immunological niches at the CNS borders and where immune cells reside and originate. Some processes of interest could involve the migration of HIV-infected cells across the blood–brain barrier, while others can be observed between neurons and CNS-resident immune cells. Notably, there are limited studies on how substances and HIV individually impact crosstalk within the CNS, and between the central and peripheral immune system. Further, our understanding of the various immunological pathways of the brain and the complex interplay between adaptive and innate immunity in the context of HIV and SUD comorbidity remains elusive and is an underexplored area of research.

Neuroimmune axes can be broadly described as the discrete cellular and anatomical sites of interaction wherein neurons, immune cells, and signaling mechanisms colocalize to regulate various physiologic processes and contribute to immune surveillance and homeostasis. Biological targets that are embedded within neuroimmune axes include orphan and atypical receptors and receptor-coupled systems with un- or poorly annotated endogenous and exogenous ligands and downstream effectors. In the context of substance use and HIV CNS pathogenesis, the role of such neuroimmune axes could represent significant opportunities for basic drug discovery and precision medicine. Therefore, a fundamental understanding of mediators and processes that coordinate neuroimmune functions that are intricately coordinated within axes will be of high significance towards understanding the impacts of substance use on CNS HIV infection.

Scientific Research Objectives and Scope

This National Institute on Drug Abuse (NIDA) NOFO uses an R21 Exploratory/Developmental Research Grant program activity code to support projects for the early and conceptual stages of project development. The initiative aims to advance research on understanding and treating SUD/HIV comorbidity, and will support research in the following scientific areas –

Immune/CNS targets, cellular and molecular mechanisms, signaling molecules, and neuroimmune responses
Characterization, function, regulation, and modulation of neuroimmune interactions
Profiling tools/technologies, chemical probes, validation of mechanisms, and modulation of neuroimmune axes
Specific to this NOFO, related sub-topics of programmatic interest include, but are not limited to:

Cell-cell interactions of neurons (central and peripheral) and immune cells (resident or infiltrating) and modification by HIV and addictive substances
Contributions of afferent and efferent CNS/immune targets/cells and signaling in homeostatic control, imbalance, neurobiological and cognitive dysfunction, and repair, and impact of substances on combination antiretroviral therapy (cART) and HIV infection
Role of brain barrier interfaces and CNS border compartments in the regulation of neuroimmune responses, during substance use, cART, and acute/chronic/reactivated HIV
Neuroimmune transcriptome profiles, cellular milieu and immune cell diversity, trafficking, and migration associated with HIV pathogenesis and SUD co-occurrence
Dynamics of cells and neuroimmune interactions in disease progression (e.g., time since HIV infection, duration of substance exposure, and impact of acute withdrawal)
Regulation of neuronal circuit functions and/or synaptic plasticity by immune cells and immune signaling pathways in the context of HIV/SUD comorbidity
Molecular mechanisms and biomarkers associated with other contextual factors influencing neuroimmune function (e.g., aging, sleep deprivation, psychosocial stress)
Novel therapeutic paradigms for manipulating neuroimmune function; discovery of chemical probes/tools and biologics with neuro-immunomodulatory properties
Mechanistic studies using currently available pharmacotherapies targeting neuroimmune regulation of neurological disorders, in the context of HIV and substance use
When developing applications, applicants are strongly encouraged to further review the guidelines listed below. Applications that do not adhere to these scientific criteria may be considered as low priority projects by NIDA Program staff -

When identifying/studying neuroimmune axes, applications are strongly encouraged to address and/or delineate the bidirectional nature of the neuroimmune interactions, and the reciprocity of brain-immune axis regulation that drives adaptive mechanisms within the CNS
Applications studying enteric neuroimmune crosstalk, microbiome-neuroimmune signatures, neuro-immune-metabolic interactions and/or neuroendocrine-neuroimmune interactions, are strongly encouraged to focus on understanding mechanisms of CNS function/dysfunction, and neuroimmune interactions that occur at brain barrier sites and/or CNS borders/interfaces, identification of inherent regulatory targets/pathways, and discovery/utilization of novel chemical probes(s)/tool(s)
Applications utilizing humanized in vitro models are encouraged to capture a range of cellular contexts; from cell-to-tissue-to-organ-to-system, while considering the anatomical and physiological complexities of the microenvironment and brain-immune ecosystem
When studying compound effects (e.g., misused substances, cART, neuroimmunomodulatory agents, either as single compounds or combinations) using appropriate HIV models, applicants are encouraged to consider potential multi-pathway drug interactions and experimental parameters that may influence reproducibility and replicability
As reference, applications may propose research using any of the misused substances, as single compounds or combinations, selected from opioids including fentanyl and heroin, cannabis and cannabinoids, nicotine, cocaine, and psychostimulants including amphetamine and methamphetamine, depressants, hallucinogens including psychedelics, sedatives/tranquilizers, inhalants, anabolic steroids, and psychiatric medications
Applicants are encouraged to propose research that extends beyond the current knowledge on neuroimmune axes to address specific processes and/or causal links to HIV-associated neurological sequelae that is exacerbated by substance use, and studies that can identify therapeutic targets/compounds
It is anticipated that compelling projects will utilize integrated and multidisciplinary approaches. Applicants are hence encouraged to recruit research personnel with diverse backgrounds (e.g., HIV/AIDS, immunology, addiction science, chemical biology) and expertise to foster exchange of methods and tools