Notice of Intent to Publish a Funding Opportunity Announcement for Novel Preclinical Models of NeuroHIV in the cART Era (R61/R33 - Clinical Trial Not Allowed)

Key Dates

None

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute of Mental Health (NIMH)

The National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with the National Institute of Mental Health (NIMH), intends to promote a new initiative by publishing a Notice of Funding Opportunity (NOFO) to solicit applications that propose the development and early stage validation of novel humanized small animal models and/or human cellular microphysiological systems for NeuroHIV preclinical research. The goal of this initiative is to promote a significant improvement in the translational relevance of NeuroHIV models, specifically in the context of chronic HIV infection of the central nervous system (CNS) in the modern antiretroviral therapy (ART) era under conditions of viral suppression.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. 

The NOFO is expected to be published in Summer 2024 with an expected application due date in Fall 2024.

This NOFO will utilize the R61/R33 activity code. Details of the planned NOFO are provided below.

Background: The Need for More Translationally Relevant NeuroHIV Models in the ART Era

Early in the HIV pandemic, before the advent of ART, HIV-associated encephalitis and dementia dominated the clinical picture of NeuroHIV, both of which were largely caused by the neuroimmune response to high levels of acutely expressed HIV proteins. In the ART era, however, the clinical spectrum of CNS dysfunction in people with HIV (PWH) has now evolved- HIV dementia cases have drastically declined, with a significant proportion of PWH instead presenting with more mild neurocognitive impairment and mental health issues without the classical signs of HIV-related encephalopathy.

To date, the majority of NeuroHIV preclinical research has focused on the impact of actively replicating virus using small rodent and cell culture models that mimic HIV encephalitis prior to the advent of ART (i.e., animal and cell culture models that involve the acute administration and/or overexpression of specific HIV proteins at high levels). But with this new phase of the HIV pandemic, there is now a critical need for next generation NeuroHIV preclinical models that more accurately portray CNS dysfunction in the context of an ART-suppressed chronic infection. 

Research Scope

This initiative will solicit R61/R33 applications that propose to generate novel NeuroHIV preclinical models that better recapitulate CNS-immune system interactions in the context of ART-mediated chronic HIV suppression. To this end, applicants will be asked to propose a humanized small rodent model or in vitro microphysiological model that contains one or more of the following potential features:

• Human peripheral immune cells that support a natural route of HIV entry across the blood-brain barrier (BBB) into the CNS (i.e., T cells, monocytes/macrophages)
• Human glial cell types relevant to the neuropathogenesis of chronic HIV infection (i.e., microglia, astrocytes, oligodendrocytes).
• Human neurons
• Brain microvascular endothelial cells that compose the BBB

General Structure of this R61/R33 Funding Opportunity

During the R61 phase of the project, investigators will establish the model, show the presence/survival of selected human cell types, and demonstrate acute HIV infection of human CNS cells. During the R33 phase, preliminary characterization and/or phenotyping of the model in the context of ART-mediated chronic viral suppression will be performed. Phenotypes of interest include outcomes related to synaptic structure, function, and neurotransmission; neuroimmune dysfunction; BBB integrity and other cerebrovascular readouts; chronic neuroinflammation (both brain-infiltrating peripheral cells and brain-resident innate immune function); chronic neurodegeneration and AD/ADRD-relevant phenotypes; oxidative and metabolic stress; cellular senescence; and HIV reservoir establishment and chronicity. Investigators will be required to propose milestones that will serve as a go/no-go checkpoint guiding the transition from the R61 to R33 phase. Applications will also be required to include a detailed plan for preclinical model scalability and dissemination to the NeuroHIV research community, preferably via the early planning of a partnership with a commercial vendor and/or small business following project completion. 

Funding Information

Public/State Controlled Institution of Higher Education
Private Institution of Higher Education
Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
Small Business
For-Profit Organization (Other than Small Business)
State Government
Indian/Native American Tribal Government (Federally Recognized)
County governments
Independent school districts
Public housing authorities/Indian housing authorities
Indian/Native American Tribally Designated Organization (Native American tribal organizations (other than Federally recognized tribal governments)
U.S. Territory or Possession
Indian/Native American Tribal Government (Other than Federally Recognized)
Non-domestic (non-U.S.) Entity (Foreign Organization)
Regional Organization
Eligible Agencies of the Federal Government

Applications are not being solicited at this time. 

Inquiries

Please direct all inquiries to:

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

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