Research on the Neuro-Immune Axis in the context of HIV and Substance Use (R01 Clinical Trial Not Allowed)

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.