Mechanisms of Reciprocal Interactions between HIV Associated Neuroinflammation and CNS Persistence: Implications in HIV Neuropathogenesis and Cure (R01 Clinical Trial Not Allowed)

Grants @The National Institutes of Health (NIH) in Digital health & health technologies , in Mental health & wellbeing , in Non-communicable diseases , in One Health
  • Post Date : June 18, 2024
  • Apply Before : November 9, 2024
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Email Opportunity

Opportunity Description

The goal of this Notice of Funding Opportunity (NOFO) is to examine mechanisms of reciprocal interactions between HIV-associated neuroinflammation and central nervous system (CNS) HIV persistence. In particular this NOFO encourages research focused on defining the role and mechanisms of defective proviruses, HIV proteins and/or nucleic acids in inducing inflammation, immune activation and CNS co-morbidities. The impact of neuroinflammation in regulating CNS reservoir dynamics is also an area of interest. Novel therapeutic strategies targeting the reciprocal impact of persistent virus and associated neuroinflammation in the CNS compartment is also an area of high priority for this initiative.  State-of-the-art CNS cell systems, organoid models, post-mortem tissue, animal models and single-cell technologies can be used as potential tools to address this research area.  Basic and Translational research in domestic and international settings are also of interest. Multidisciplinary research teams and collaborations are encouraged but not required. High risk/high payoff projects that lack preliminary data may be most appropriate for the companion R21 NOFO, RFA-MH-25-181 while applicants with preliminary data may wish to apply using this R01 mechanism.

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply – Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply – Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply – Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply – Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background:

HIV cure research is a top priority for the NIH, and the institutes supporting this funding opportunity including NIMH Division of AIDS Research (DAR), the NINDS NeuroHIV research program, and the NIDA HIV Research Program. All the participating institutes in this NOFO are engaged in advancing cure studies to eradicate or silence HIV from reservoirs in the CNS where the virus may evade detection and treatment. In addition to understanding HIV persistence under ART, this funding opportunity also is focused on advancing knowledge about the mechanisms contributing to HIV-associated comorbidities, including CNS comorbidities (e.g., cognitive deficits, mental illnesses, cerebrovascular disease, and other neurodegenerative disease states).

A critical gap exists in understanding the factors that drive ongoing neuroinflammation and HIV persistence in the setting of effective ART. HIV-infected individuals on effective ART may experience ongoing immune activation and neuroinflammation, which may result in HIV-associated comorbidities. While most integrated proviral DNA is defective it may continue to be a source of HIV RNA and protein expression derived from infected CNS cells (eg macrophages, microglia, astrocytes) contributing to chronic neuroinflammation even with full suppression of ongoing viral replication.

Single-cell-based technologies and novel sequencing methods now make it possible to better define HIV RNA and proteins expressed from intact and defective proviruses, as well as to determine their roles in inflammation, immune activation and in HIV persistence.

Residual levels of viral replication during ART are associated with persistently low levels of immune activation, which can promote the replenishment of the HIV reservoir in the CNS. Chronic inflammation might lead to HIV persistence by causing virus production, generating new target cells (cells targeted for viral infection), enabling infection of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms. A vicious cycle of HIV persistence and neuroinflammation may exist and there is a critical need for novel therapeutic strategies addressing these interactions.

This NOFO aims to examine mechanisms of reciprocal interactions between HIV-associated neuroinflammation and CNS HIV persistence. This initiative encourages the use of novel model systems such as brain organoids, iPSC- (induced pluripotent stem cell) derived microglia, astrocytes, animal models, post-mortem tissues and state-of-the-art single-cell methodologies.

The use of human post-mortem specimen resources from large NIH-funded HIV-related studies are encouraged. An example of such a resource is the

Examples of research areas that fall within the scope of this NOFO include, but are not limited to

  • Studies of mechanisms of neuroinflammation in CNS-derived cells driven by defective proviruses, viral proteins, and RNA in the context of viral suppression Examples include studies of innate immune activation, inflammosomes, interferon mediated chronic immune activation and inflammation.
  • Identification of mechanisms of the impact of neuroinflammation and immune dysfunction on HIV persistence in CNS.
  • Studies investigating potential crosstalk between blood-brain barrier (BBB)-associated endothelial inflammation, glial-mediated neuroinflammation, and HIV viral dynamics and persistence.
  • Defining the role of co-infections/opportunistic infections (cryptococcosis, tuberculosis, herpes virus, polyomavirus, cytomegalovirus) and associated neuroinflammation on HIV CNS reservoirs.
  • Defining mechanisms of the impact of latent/persistent viral HIV reservoirs on immune homeostasis in the CNS and the impact of these latent/persistent reservoirs on neurotransmitters, neuronal function, and neuronal plasticity.
  • Studies of mechanisms driving the crosstalk between neuronal activity, neuroinflammation activation states and HIV reservoir dynamics.
  • Development of therapeutic strategies to alleviate the reciprocal impact of persistent virus and associated neuroinflammation in the CNS compartment.

Successful completion of these studies may advance our understanding of the mechanisms of HIV neuropathogenesis and persistence to help achieve an HIV cure.

NIDA will consider applications that address the influence of addictive substances or relevant signaling pathways on mechanisms of HIV associated neuroinflammation and viral persistence, with a particular focus on the central nervous system reservoirs. Studies utilizing biological samples from individuals who use addictive substances (nicotine, cocaine, psychostimulants, opioids, prescription drugs, cannabinoids, psychedelics, or combinations of alcohol and addictive substances) are highly encouraged.

The following studies will be considered non-responsive for this announcement and will not be reviewed:

  1. Studies focusing exclusively on CD4 T cells
  2. Studies focusing exclusively on peripheral derived cell populations without including CNS derived cells
  3. For studies focused on mechanisms of HIV neuropathogenesis driven by HIV CNS reservoirs:
    • Approaches that do not consider the impact of ART in basic and clinical settings
    • Outcomes based solely on broad behavioral assays without inclusion of measures of associated brain processes in basic and clinical settings

See Section VIII. Other Information for award authorities and regulations.

Additional Information on the opportunity

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