Key Dates

Related Announcements

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• 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 - Emerging Global Leader Award (K43 Independent Clinical Trial Required). See NOFO PAR-21-251
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• 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
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Issued by

National Institute of Mental Health (NIMH)

National Institute of Neurological Disorders and Stroke (NINDS)

Purpose

This Notice of Special Interest (NOSI) invites research grant applications studying mechanisms of HIV-1 persistence and eradication strategies specifically focused on the central nervous system (CNS) in the context of viral suppression. Basic and translational research in domestic and international settings are of interest. Multidisciplinary research teams and collaborative alliances are encouraged but not required.

Background

Anti-retroviral therapy (ART) can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in persons living with HIV, but it fails to eliminate the virus due to the presence of latent reservoirs. There is now a major push in the field of HIV research to target latent reservoirs to achieve sustained virologic remission. The question of whether the brain is a reservoir for replication competent HIV is currently an area of great interest. The long-lived cells in the CNS, including astrocytes, perivascular macrophages and microglia, have been shown to support both HIV infection and variable levels of replication. There is also evidence of compartmentalized viral evolution in the brain, suggesting that independent HIV replication can occur in the CNS and these brain variants can potentially reseed the periphery. Therefore, it is critical to study the role of CNS resident cells as potential cellular viral reservoirs, and how persistently infected cells in the CNS tend to persist despite ART. The molecular mechanisms involved in the establishment, maintenance, and resurgence of CNS-based HIV reservoirs in relationship to the effects and timing of ART represents a major gap in the field.

Eradicating HIV-1 from persistent reservoirs in an effort to find innovative strategies to cure HIV-1 infection is a high research priority for NIMH.  In addition to the ongoing HIV-1 eradication efforts targeting the periphery, research is needed to specifically target viral reservoirs in the CNS because of unique anatomic features in the brain, such as the blood-brain barrier and enclosure within the restricted skull cavity. One of the key challenges for eradication of HIV-1 reservoirs is the development of strategies and approaches that can penetrate the blood-brain barrier. The currently popular strategy for HIV eradication has been the “shock and kill approach”, which may have detrimental effects in the CNS due to neuronal toxicity and inflammatory sequelae resulting from reactivation of virus. Therefore, there is a need for discovery research focused solely on expanding our knowledge base of CNS HIV-1 latency and eradication strategies tailored directly for the brain compartment. These may also include approaches to target latent CNS infection using viral silencing approaches rather than reactivation strategies.

There is considerable interest in the development of immunotherapy to optimize the recognition and killing of reservoir cells such as resting CD4 T-cells. These immunotherapy strategies include uses of therapeutic vaccines to enhance HIV-1-specific CTL (cytotoxic T-cell) response, broadly neutralizing antibodies, dual-affinity retargeting antibodies that not only bind to HIV-1 viral envelope antigen but also activate the CTL response, and immune modulators, such as anti-PD1 (programmed cell death protein-1) or anti-CTL4 antibodies, to relieve the immune dysfunction and exhaustion found in cART-treated individuals due to chronic inflammation. Another strategy is the development of chimeric antigen receptor T-cells (CAR-T cells) to target latently infected cells. Current immunotherapy-based HIV eradication strategies are focused primarily on peripheral sites and it is important to target CNS reservoirs as well. Further, it is also critical to understand the potential CNS toxicity of immunotherapy-based approaches currently being tested in clinical trials.

Research Objectives and Scope

Examples of the CNS-specific research focus areas that are pertinent to this NOSI include, but are not limited to, the following:

• Identify all potential cellular reservoirs of latent HIV-1 within the CNS (e.g., macrophages, microglia, astrocytes, T-cells);
• Discover the molecular mechanisms involved in establishment, maintenance, and resurgence of CNS-based HIV-1 reservoirs in relationship to the effects and timing of ART;
• Elucidate how persistently infected cells of the CNS escape the immune response and persist despite ART;
• Examine the role of CNS inflammation in maintaining HIV persistence within this compartment;
• Design new assays and in vitro and in vivo model systems, including a non-human primate model as appropriate, to study HIV latency;
• Develop physiologically relevant CNS-cell based assays that recapitulate: HIV-1 persistence in the presence of effective antiretroviral therapy; latency; and viral resurgence upon removal of ART;
• Identify and develop assays to quantify levels of residual latent and replication-competent virus and residual viral replication in the CNS compartment in patients on suppressive anti-retroviral therapy;
• Develop innovative strategies to selectively identify (i.e., using biomarkers, cell surface antigens, molecular signatures) and eliminate latently infected CNS-derived myeloid cells (e.g., microglia) without reactivation of pro-virus;
• Refine neuroimaging or microscopic technologies to detect latent/persistent and reactivated virus in the CNS compartment;
• Determine new cell surface and intra-cellular markers that identify latently infected cells in the CNS using state-of-the-art proteomic or metabolomics approaches;
• Develop high throughput assays or refine physiologically relevant primary cells for use in identifying drug candidates for eradication of HIV-1 in the brain;
• Assess current HIV-1 eradication strategies for CNS toxicity, neuroinflammation, and neurocognitive outcomes;
• Develop novel eradication strategies with improved penetration through the blood-brain barrier to target and eliminate latent CNS reservoirs (e.g., gene therapy, nanotechnology, zinc finger technology);
• Develop a new class of delivery agents that can increase the bioavailability of drugs within the CNS and target HIV-1 infected cells;
• Identify novel strategies to prevent viral resurgence in the CNS upon cessation of ART;
• Develop innovative strategies including gene editing based approaches, to selectively identify and eliminate virus and the latently infected cells without reactivation of provirus;
• Develop unique classes of HIV drugs that inhibit viral production from stable reservoirs and reduce residual viral presence in the periphery and the CNS;
• Refine and adapt immunotherapy-based therapeutic strategies to target CNS reservoirs using approaches such as CAR-T-cells, NK cells, check point inhibitors, therapeutic vaccines and broadly neutralizing antibodies;
• Studies of epigenetic factors regulating HIV latency in CNS derived cells and development of therapeutic strategies for deep silencing of HIV by targeting epigenetic pathways in CNS derived cells

For applications that propose clinical trials, the planned studies should be consistent with the NIMH experimental therapeutics approach and applications are required to provide a strong theoretical rationale for the selected targets or mechanisms of action hypothesized to lead to the intended outcomes (see Support for Clinical Trials at NIMH).

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, NINDS is interested in the majority of the research areas identified above. While the NINDS will support studies focused on the effect of chronic HIV on cognitive outcomes and neurological disorders, applications that are solely interested in mental health and psychiatric outcomes will not be supported by the NINDS. This includes applications that solely rely upon RDoC-based constructs for neurobehavioral analyses. Rather, the 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. In addition, only mechanistic clinical trials and Basic Experimental Studies with Humans (BESH) will be supported by the NINDS under this NOSI. Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions will not be supported under this NOSI.

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 

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.

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 (NOFOs) or any reissues of these announcement through the expiration date of this notice. 

 All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-MH-23-260” (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 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)

Jeymohan Joseph, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 240-627-3869
Email:jjeymoha@mail.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

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