Key Dates

Related Announcements

• May 08, 2023 - NINDS Postdoctoral Mentored Career Development Award (K01 Clinical Trial Required). See NOFO PAR-23-142
• May 08, 2023 - NINDS Postdoctoral Mentored Career Development Award (K01 No Independent Clinical Trial Allowed). See NOFO PAR-23-143
• January 26, 2023 - Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (Parent T32). See NOFO PA-23-048
• September 08, 2021 - NIMH Exploratory/Developmental Research Grant (R21 Clinical Trial Not Allowed). See NOFO PA-21-235
• September 08, 2021 - Emerging Global Leader Award (K43 Independent Clinical Trial Required). See NOFO PAR-21-251 
• September 08, 2021 - Emerging Global Leader Award (K43 Independent Clinical Trial Not Allowed). See NOFO  PAR-21-252 
• May 19, 2021 - Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 Clinical Trial Required). See NOFO PAR-21-154
• May 19, 2021 - Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 Clinical Trial Not Allowed). See NOFO PAR-21-155
• May 10, 2021 - Joint NINDS/NIMH Exploratory Neuroscience Research Grant (R21 Clinical Trial Optional). See NOFO PA-21-219
• May 07, 2021 - NIMH Research Education Mentoring Program for HIV/AIDS Researchers (R25 Clinical Trial Not Allowed). See NOFO PAR-21-228 
• April 23, 2021 - NINDS Faculty Development Award to Promote Diversity in Neuroscience Research (K01 Independent Clinical Trial Not Allowed). See NOFO PAR-21-234
• April 8, 2021 - NINDS Faculty Development Award to Promote Diversity in Neuroscience Research (K01 Clinical Trial Required). See NOFO PAR-21-153
• October 28, 2020 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (Parent F31-Diversity). See NOFO PA-21-052
• October 26, 2020 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (Parent F32). See NOFO PA-21-048  
• October 26, 2020  - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship for Students at Institutions Without NIH-Funded Institutional Predoctoral Dual-Degree Training Programs (Parent F30). See NOFO PA-21-050
• October 26, 2020 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (Parent F31). See NOFO  PA-21-051
• October 15, 2020 - NINDS Ruth L. Kirschstein National Research Service Award (NRSA) for Training of Postdoctoral Fellows (F32 Clinical Trial Not Allowed). See NOFO PAR-21-032
• May 12, 2020 - Mentored Clinical Scientist Research Career Development Award (Parent K08 Independent Clinical Trial Required). See  NOFO PA-20-202
• May 12, 2020 - Mentored Clinical Scientist Research Career Development Award (Parent K08 Independent Clinical Trial Not Allowed). See  NOFO PA-20-203
• May 12, 2020 - Mentored Patient-Oriented Research Career Development Award (Parent K23 Independent Clinical Trial Not Allowed). See NOFO  PA-20-205 
• May 12, 2020 - Mentored Patient-Oriented Research Career Development Award (Parent K23 Independent Clinical Trial Required). See NOFO PA-20-206 
• May 7, 2020 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed). See NOFO PA-20-200
• May 6, 2020 - Mentored Research Scientist Development Award (Parent K01-Independent Clinical Trial Required). See NOFO PA-20-176
• May 6, 2020 - NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Required). See NOFO PA-20-187
• May 6, 2020 - NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Not Allowed). See NOFO PA-20-188 
• May 6, 2020 - Mentored Research Scientist Development Award (Parent K01--Independent Clinical Trial Not Allowed). See NOFO PA-20-190
• May 6, 2020 - Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Required). See  NOFO PA-20-193
• May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Required). See NOFO PA-20-183 
• May 5, 2020 - NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required). See NOFO PA-20-184
• May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185
• May 5, 2020 - Midcareer Investigator Award in Patient-Oriented Research (Parent K24 Independent Clinical Trial Not Allowed). See NOFO  PA-20-186

Issued by

National Institute of Mental Health (NIMH)

National Institute of Neurological Disorders and Stroke (NINDS)

Purpose

The goals of this NOSI are to stimulate further research on delineating the pathophysiology of HIV-1 associated Central Nervous System  (CNS) complications in the setting of chronic viral suppression and antiretrovial therapy (ART). In addition, this NOSI also encourages research studies to aid in the identification/ validation of biomarkers with quantifiable readouts in domestic and international settings. Multidisciplinary research teams and collaborative alliances are encouraged but not required.

Background:

Central Nervous System complications associated with HIV continues to persist in people with HIV (PWH) despite effective ART. Although excellent virologic control in the periphery and brain has been achieved, CNS disease (NeuroHIV) including neurologic, neurocognitive, and mental health problems are observed. Considerable gaps exist in our understanding of pathogenesis of CNS disease associated with HIV. The current understanding of pathogenesis of CNS complications in PWH is largely based on clinical phenotypes that were predominantly observed prior to the ART era or from the time when  patients were transitioning to using ART. Researchers are now recognizing that, in addition to inflammation at the cellular level, various individual-level factors such as comorbid conditions, concomitant neurological diseases, persistent CNS viral reservoirs, long-term effects of living with HIV, immune system dysfunction, social and structural factors, concomitant drug use and ART-related toxicity can influence CNS pathogenesis and resulting outcomes.

Basic research in the NeuroHIV field has primarily focused on modeling neuronal damage in the context of active viral replication or the impact of HIV proteins such as Tat/gp120, with endpoints such as encephalitis and neuronal death. However, the CNS disease outcomes observed in the pre-ART era, such as atrophy and encephalitis, are not apparent in the current era. It is plausible that other mechanisms, such as neuroimmune dysfunction, legacy effects of long-term ART medications and chronic inflammation, in the context of co-morbidities, may play a role in the observed HIV-associated CNS disease outcomes. Other potential unexplored mechanisms and pathways may drive the development of CNS disease, such as subtle neuro-metabolic changes, alterations in neuronal circuitry, or altered signal transmission. In addition, psychological, social, and structural factors may interact with these biological mechanisms, to further impact outcomes. Novel research directions could include studies of factors related to neural membrane channel function, neurotransmitter trafficking, synaptic plasticity, and neural activity anomalies. The role of extracellular vesicles (EVs) and micro RNAs in modulating the micro-environment around the synapse is also of interest.

Viral and host genetic factors contribute to pathophysiology of HIV-1associated CNS disease. New genetic technologies may complement the effort to provide unique perspectives on the neuropathology and aid in the identification of innovative strategies for the discovery of therapeutic drug targets. GWAS data available from a reasonably large number of PWH from several large cohorts (e.g., CHARTER, MWCCS) can be utilized to understand how host genetics impacts the development/progression of CNS complications associated with HIV. The use of state-of-the-art genetic approaches (including transcriptomics, phenomics, epigenomics, single cell genomics, whole genome association studies, ultra-deep sequencing, exome sequencing, and systems biology) as well as the use of human sample resources and animal model systems are encouraged to study and validate viral and host genetic contributions to HIV neuropathogenesis.

There are several in vitro and in vivo models being used to investigate the pathogenesis of HIV associated CNS outcomes, but these models have limitations in their ability to mimic current clinical phenotypes. Additional research is needed to develop better models that consider the effect of chronicity of viral infection, persistence of the viral reservoir, ART toxicity and co-morbidities. There is also a need for appropriate models to validate potential therapeutics for HIV-1 associated CNS complications.

In summary, the goals of this NOSI are to stimulate further research on delineating the pathophysiology of HIV-1associated CNS disease in the setting of chronic viral suppression and ART.

Areas of Research Interest:

The research areas that are pertinent to this NOSI include, but are not limited to:

Pathogenesis of HIV-1 associated CNS disease in the context of ART

• Basic research on neuronal disease focusing on neuronal receptors, neurotransmitters, neural activity, neural circuits and synapto-dendritic damage;
• Studies to understand and decipher at a molecular level, how neuroimmune dysregulation caused by HIV impacts neuronal receptors, neurotransmitters and synaptic plasticity;
• Studies to assess the role of extracellular vesicles and micro-RNAs in context of neuroimmune dysfunction caused by HIV as well as evaluate the potential role of exosomes as biomarkers for HIV-1 associated CNS complications;
• Studies to identify molecular and cellular mechanisms underlying neurological impairment in acute and early infection in addition to assessing the impact on early initiation of treatment on immune recovery and resulting long term neurological outcomes;
• Studies to assess the impact of metabolic disturbances related to long term ART on CNS outcomes among HIV-1 infected patients including but not limited to studies on the effect of insulin resistance, lipid abnormalities and mitochondrial disease on HIV-associated CNS disease;
• Studies to model the contributions of non-infectious co-morbidities (vascular, stroke, epilepsy) to HIV-1 associated CNS disease and reciprocal interactions of HIV-1 associated CNS disease with other neurodegenerative diseases;
• Basic studies to understand the neuropsychiatric adverse events and potential CNS toxicities associated with ART and other emergent treatments such as immunotherapy;
• Basic studies to understand how peripheral immune cells (Such as T cells or macrophages) or CNS-resident immune cells (Such as Microglia and Astrocytes) influence neuronal function in the context of HIV and ART;
• Studies to determine the modulatory effects of immune dysfunction and chronic inflammatory changes caused by HIV in the context of ART on neuronal circuits, neurotransmitters, and their connections with other systems, such as the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine system;
• Studies to understand the impact of chronic immune activation and immune dysfunction in the periphery and the CNS caused by HIV and ART on the blood-brain barrier and its impact on neuronal function;
• Basic studies to identify mechanisms by which gut microbiota and gut immune system altered by HIV impact CNS outcomes in people with HIV on ART;
• Studies that model the impact of HIV and associated gut immune dysfunction on neurotransmitters, brain circuits, and networks regulating mood, cognition, and behavior;
• Studies that propose to generate and validate novel in-vivo animal and in-vitro cell culture models to address the above questions.  

Viral Genetics and Host Genetics factors influencing CNS outcomes in PWH:

• Studies of the role of HIV-1 sequence diversity in understanding neurovirulence, neurotropism, discordant and compartmentalized viral evolution, CNS cell type-specific infection, regional genetic heterogeneity, and associated functional effects;
• Studies to identify mechanistic viral genetic signatures associated with HIV associated CNS disease;
• Studies of the role of viral epigenetic factors in the pathophysiology of HIV associated CNS disease;
• Studies to understand the role of viral and host transcriptional regulation (including viral protein modifications, histone modifications, changes in chromatin structure, and non-coding RNA) in HIV neuropathogenesis.
• Studies of the role of host genetic factors, including epigenetic mechanisms in regulating susceptibility to HIV-1 associated CNS disease;
• Studies to assess epigenetic host response to viral infection mediated through chromatin modification, non-coding RNAs, and DNA methylation in CNS resident cells;
• Studies of host genetic factors involved in regulating responsiveness to antiretroviral therapy and neuroprotective adjuvant therapies (pharmacogenomics);
• Studies to delineate the genetic basis of host restriction factors in CNS cell types that impact HIV replication.

Applicants proposing animal studies in response to this NOSI should consider NIMH guidelines and priorities regarding animal neurobehavioral approaches in research relevant to mental illnesses as detailed in NOT-MH-19-053 and the recent commentary, "A Hypothesis-Based Approach: The Use of Animals in Mental Health Research". Bio-behavioral studies being proposed in response to this NOSI should consider NIMH guidelines and priorities in the field of stress biology research as detailed in NOT-MH-18-058.

NINDS Research Interests:

NINDS supports research on the brain and nervous system and uses that knowledge to reduce the burden of neurological disease. In the context of HIV disease and for the purposes of this notice, the NINDS is interested in the majority of the research areas identified above. Research of particular interest would include: studies of the mechanisms by which chronic HIV exacerbates long term blood-brain barrier (BBB) damage and cerebrovascular dysfunction in the context of stroke and vascular contributions to cognitive impairment and dementia (VCID); studies of the mechanisms by which chronic HIV might prime the CNS for neurodegeneration including in the context of AD/ADRD; research focused on potential interactions between chronic HIV infection and other neurological disorders within the mission of NINDS and projects that address the mechanisms of HIV-associated peripheral neuropathy/chronic pain. Applications that are solely interested in mental health and psychiatric outcomes (using RDoC framework) will not be supported by NINDS. NINDS strongly prefers the incorporation of additional multidimensional measures of neurological function, such as the NIH Toolbox for the assessment of cognitive, motor, and sensory function, in combination with other mental health-related measures. 

NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable: rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications

Note:

Prospective applicants are strongly encouraged to contact the Scientific Program Contacts listed below before preparing an application to discuss the relevance of the proposed research to the Institute's research priorities.

Applications to this NOSI are strongly encouraged to integrate at least two levels of analysis (e.g. behavior/cognition, neural circuits, genetics, molecular and cellular processes) and use approaches to study discrete neurobiologically-linked behavioral constructs (RDoC Framework, NIH Toolbox, and/or Neuro-QoL-based assessments).  Use of humanized animal models and brain organoids that can mimic the pathophysiology of HIV infection are highly encouraged. Pathogenesis  studies using model systems primarily focused on single viral gene products (such as HIV-1 Tat/gp120) in isolation and models of infection using chimeric HIV variants that do not represent the complete gamut of downstream neuropathogenic mechanisms related to HIV will NOT be supported under this NOSI.

The use of human specimen resources from large NIH-funded HIV-related studies is encouraged.

Examples of such studies include, but are not limited to:

• MACS/WIHS Combined Cohort Study;
• CNS HIV Antiretroviral Therapy Effects Research (CHARTER);
• AIDS Clinical Trials Group (ACTG); and the
• National NeuroAIDS Tissue Consortium (NNTC) 

This notice applies to due dates on or after September 7, 2023 and subsequent receipt dates through September 8, 2026.

Submit applications for this initiative using one of the following Notices of Funding Opportunities announcements (NOFOs) or any reissues of these announcements through the expiration date of this notice. 

 All instructions in the SF424 (R&R) Application Guide and the Notice of Funding Opportunity (NOSI) f  used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-MH-23-280” (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 not be considered for the NOSI initiative.

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

Inquiries

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed notice of funding opportunity.

 Scientific/Research Contact(s)

Vasudev R Rao, MBBS, MS.
National Institute of Mental Health (NIMH)
Telephone: 301-825-3259
Email: vasudev.rao@nih.gov

William Daley, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1431
Email: william.daley@nih.gov

Financial/Grants Management Contact(s)

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email:siscor@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov