Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

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.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Despite the successful advent of antiretroviral therapies (ART), CNS dysfunction associated with HIV infection continues to persist in up to 30-50% of people with HIV (PWH). While ART greatly reduces HIV viral load and has dramatically increased the overall survival of PWH, it does not fully eliminate residual viral reservoirs in protected regions of the body such as the CNS. As a result, continuing low levels of CNS viral infection and/or the expression of defective viral RNA transcripts may trigger chronic episodes of neuroimmune dysfunction in the brain, which in turn can cause mild to moderate neurological impairment (for example, HIV-associated neurocognitive disorder, or HAND, and other neuropsychiatric complications). 

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 expression of specific HIV proteins). But with this new phase of the HIV pandemic, there is now a critical need to more accurately model CNS dysfunction in the context of an ART-suppressed chronic infection. In addition, an increasing number of studies have demonstrated the neurotoxic effects of some ART therapies themselves, which further highlights the necessity for ART consideration in future NeuroHIV preclinical modeling studies. And although a number of nonhuman primate models have been established for this purpose, these are very expensive, require specialized facilities and expertise, and have become increasingly difficult to procure. 

In recent years, immunodeficient mouse models with reconstituted human immune systems have become state of the art in the NeuroHIV field. One advantage of such models is that they are permissive to natural HIV infection via peripheral routes, with the virus then crossing the blood-brain barrier (BBB) at acute timepoints. Humanized rodent models have provided new information regarding the establishment of latent HIV infection in the CNS following ART-induced suppression, with some models now incorporating human microglia and astrocytes, both of which support viral reservoirs in the brain that can reconstitute a peripheral infection upon ART withdrawal. Likewise, in vitro human microphysiological models have also gained traction in the NeuroHIV research community with the recent incorporation of HIV-susceptible microglia into 3D brain organoids and the demonstration that these organoids support enhanced levels of HIV infection, inflammatory cytokine production, and synaptic degeneration. Although significant progress has been made in leveraging small animal and in vitro microphysiological models of NeuroHIV, numerous crucial deficiencies still persist that must be addressed to enhance the continued applicability of such models, particularly in the context of ART. For example, while there are now preclinical models with human microglia and astrocytes in isolation, next generation models should ideally contain multiple human CNS cell types in combination and more accurately represent the effect of a suppressed chronic infection on these cell types (and their interaction with uninfected bystander CNS cells). In addition, no NeuroHIV 3D microphysiological models to date have included a functional cerebrovasculature and other peripheral immune cell types that play a role in HIV infection of the CNS. 

Objectives and Scope

This initiative will support applications that propose to generate and characterize NeuroHIV preclinical models that better recapitulate CNS-immune system interactions in the context of ART-mediated HIV suppression. To this end, applicants will be expected to propose a small animal model or in vitro microphysiological model that supports HIV infection and incorporates some of the following potential features: 

• Peripheral immune cells that support a natural route of HIV entry across the BBB into the CNS (i.e., T cells, monocytes, etc.).
• Glial cell types relevant to the neuropathogensis of chronic HIV infection (i.e., microglia, astrocytes, oligodendrocytes, etc.).
• Neurons
• Brain microvascular endothelial cells and supporting mural cell types that compose the BBB.

While the incorporation of human cells is strongly encouraged, this is not an absolute requirement as long as the model supports infection with a replication competent virus that can be efficiently suppressed upon ART treatment. In all cases, a strong argument should be made for how the model closely mimics human NeuroHIV (even in the absence of human cell types, if applicable). This initiative will not support the generation and validation of new non-human primate models for NeuroHIV research. Nor will it support studies primarily designed to test mechanistic hypotheses about NeuroHIV disease pathophysiology in preclinical models. Rather, the knowledge and resources gained from these studies should lead to the development and validation of “next generation” NeuroHIV models that will provide an improved toolkit that more closely recapitulates the current clinical picture of NeuroHIV in ART suppressed individuals. Such models will then ideally be used by the NeuroHIV community to better inform future mechanistic and translational studies focused on the molecular, cellular, and circuit-level processes that underlie HIV-associated neurological dysfunction in the ART era. 

Phased Award Mechanism and Transition to R33

The generation and characterization of clinically relevant preclinical models typically requires a multi-step process that includes the initial development and feasibility testing of the model system followed by internal/external validation and the characterization of clinically relevant disease phenotypes. Therefore, this funding opportunity will use a phased R61/R33 mechanism.

The R61 phase will support the initial development, validation, and optimization of the NeuroHIV model. During this phase, investigators will be expected to establish the model, show the presence, survival, and functionality of key CNS cell types, demonstrate acute HIV infection of CNS cells, and determine model reproducibility and dynamic range for viral infection. During the R33 phase, preliminary characterization and/or mechanism-based phenotyping (i.e., not correlative) of the model in the context of ART suppression will be performed. Phenotypes of interest include synaptic structure, function, and neurotransmission; BBB integrity and other cerebrovascular readouts; chronic neuroinflammation (both brain-infiltrating peripheral cells and brain-resident innate immune function); chronic neurodegeneration and other relevant phenotypes of cognitive dysfunction; oxidative and metabolic stress; cellular senescence; HIV reservoir establishment and chronicity; sex- and age-dependent effects on neurological phenotypes; and the modulation of CNS phenotypes by stress and other determinants of health. In addition, applications that propose R33 phase studies to characterize the modulatory effects of addictive drugs on CNS outcomes and preliminary proof-of-concept neurobehavioral assessments of sensory-motor and cognitive function, social interactions, anxiety- and depressive-like behaviors, and drug seeking behaviors would be of particular interest to NIDA. For R33 phenotyping studies, a variety of techniques may be appropriate, including (but not limited to): single cell transcriptomic, proteomic, and metabolomic analyses; neuroinflammatory profiling and cytokine/chemokine analyses; neuroimaging and calcium imaging of neuronal circuit structure and function; electrophysiology; stereology; assays that characterize BBB permeability, cerebrovascular function, and/or brain endothelial inflammation; and assays that quantify HIV viral reservoirs. Finally, although proof of concept neurobehavioral assessments are allowed during the R33 phase, the majority of the model phenotyping should not consist of behavioral analyses. In all cases, the final outcome should be a fully validated preclinical model that can be utilized in future studies to investigate clinically relevant NeuroHIV disease mechanisms and/or to test the biological effects of candidate therapeutics for NeuroHIV in the context of a fully suppressed chronic infection. 

Applicants are required to propose milestones that will serve as a go/no-go checkpoint guiding the transition from the R61 to R33 phase, and advancement to the R33 phase will be contingent upon their successful completion. Milestones are quantifiable goals for measuring success that should have timelines and quantitative criteria associated with them. All milestones should be used as a measure of progress toward the overall goal of the project- as such, Specific Aims or a list of activities planned for each year are not considered milestones because they do not directly inform decision-making criteria.

Preclinical, Clinical, and Model Dissemination Collaborations

The demonstration of collaborative investigative teams with preclinical and clinical NeuroHIV expertise is highly encouraged. Therefore, a letter of support from a collaborating clinician which demonstrates their involvement in the project and discusses a detailed plan for collaboration with the principal investigator should be included in the application. The clinician should have demonstrated expertise in the diagnosis and/or treatment of NeuroHIV which would ideally be used to inform model development/characterization to ensure that the proposed model accurately fits the current clinical picture of NeuroHIV in the cART era. 

In addition, it is expected that new models proposed under this initiative will be widely shared with the NeuroHIV research community upon the completion of the project. To this end, applications should include a detailed discussion of preclinical model scalability and early plans for their dissemination to interested researchers, for example via the early planning of a partnership with a commercial vendor and/or small business following project completion. Since this preliminary plan may involve intellectual property (IP) considerations, a letter of support from an institutional technology transfer office representative should be included which outlines how they'll work with the principal investigator to address any issues that may arise (if applicable). 

Applications Not Responsive to this Initiative

Non-responsive applications include those that involve any of the following:

• Projects that propose significant efforts to test therapeutic strategies for the alleviation of NeuroHIV CNS outcomes.
• Applications with a primary focus on biomarker discovery and/or validation.
• Applications that propose a non-human primate model of NeuroHIV. 
• Applications that propose NeuroHIV models which do not involve infection with a replication competent virus (i.e., HIV protein overexpression or injection models are non-responsive).
• Applications that do not propose NeuroHIV model characterization in the context of ART-mediated viral suppression during the R33 phase. 
• Applications that propose only neurobehavioral analyses in the R33 phase (i.e., neurovirological analyses and neurobiological assessments of cell and molecular CNS outcomes must also be included).
• Studies that fail to include quantitative go/no-go milestones as well as a clear demarcation of which activities are in the R61 phase and which are in the R33 phase are also considered non-responsive. The R61 phase and R33 phase must not overlap in time. 

Non-responsive applications will be administratively withdrawn without review.

Additional Considerations

Applicants are strongly encouraged to consult with NINDS, NIMH, or NIDA Program staff early on during the planning stage of their application (see Agency Contacts, Section VII). This early contact will provide an opportunity to clarify the applicant's understanding of this initiative's goals, policies and guidelines.

Prior to funding an application, Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the review panel or Program staff. A final set of approved milestones will be specified in the Notice of Award.

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.

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

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Organizations)

Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply - Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

William Daley, PhD
Telephone: 301-496-1431
Fax: 301-402-2060
Email: william.daley@mail.nih.gov

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

Other Attachments:

Intellectual Property Plan: Applications must include a one-page discussion of the intellectual property (IP) landscape surrounding their proposed model, specifically as it relates to model dissemination. This discussion should be included as an attachment labeled “Intellectual Property.pdf”. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

In this section, applicants should describe the IP landscape surrounding their model, if applicable. Applicants should describe any known constraints that could impede the generation and validation of the proposed model (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar model systems that are under patent protection and/or on the market, etc.) and how these issues could be addressed in order to still achieve this program's goal of new model dissemination to the NeuroHIV research community. If the applicant proposes using a technology or agent(s) for validation purposes whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the model which would impede achieving the goals of the funding program. If patents pertinent to the model technology or validating agent(s) being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable. In addition, applicants should discuss future IP filing and model dissemination plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the program.

All instructions in the How to Apply - Application Guide must be followed.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims: Within the Specific Aims section, applicants must include headers entitled “R61 Phase Specific Aims” and “R33 Phase Specific Aims”. Under each header, state the specific objectives of that phase of the project. Briefly provide the context and overall rationale for the proposed set of studies, with an emphasis on the reason that the proposed model will significantly improve the translational quality of NeuroHIV preclinical research in the cART era. In addition, the major objectives of the proposed set of studies should be stated, including the technical questions to be answered to determine the feasibility and the validity of the proposed model system.

As this is an R61/R33 mechanism, clear demarcation of which activities are in the R61 phase and which are in the R33 phase is required (the two phases should not overlap in time). Applications that do not propose both an R61 and R33 phase will be administratively withdrawn without review.

Research Strategy: The Research Strategy section must include the following information.

Model Rationale and Unmet Need

• Biological and translational rationale for the proposed model as it relates to the current knowledge of NeuroHIV disease etiology in the cART era (i.e., how well the model system will recapitulate the neurological deficits, pathology, and disease progression of NeuroHIV in the cART era; brief discussion of future translational/clinical value).
• Strengths and weaknesses of the prior research used to support the proposed NeuroHIV model. This may include the applicant’s own preliminary data, data published by the applicant, or data published by others.
• Key advantages of the proposed NeuroHIV model over alternatives already available in the field (i.e., description of the unmet need for the proposed model).

Experimental Approach

• Description of how the model will be produced and optimized, including a plan to confirm the identity and survival of CNS cell types and their ability to support HIV infection with a replication competent virus.
• If the proposed NeuroHIV model requires breeding or aging, evidence must be presented that sufficient animals will be available to conduct rigorous model characterization and validation studies within the 4-year limit of the funding period.
• Detailed plans for the assays and neurological endpoints that will be used to characterize clinically relevant neurological phenotypes in the proposed NeuroHIV model in the context of cART.

Milestones

• Transition from the R61 to the R33 phase is contingent upon the successful completion of one set of proposed milestones. The specific milestone(s) proposed in the application will depend on the proposed model and the accomplishments necessary in the R61 phase for advancement of the model into the phenotyping and validation studies proposed for the R33 phase. These milestones are to be included in their own subsection of the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R61/R33 application. 
• The milestones proposed in the application should be well-described, concrete, and scientifically justified. In addition, a strong rationale should be provided for the choice of measures and values proposed for the milestones. Specific aims or a general list of activities are not considered milestones because they would not provide decision-making criteria in and of themselves. Rather, the proposed milestones should provide clear and quantifiable indicators of the R61 phase's success or emergent difficulties since these will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the Program Director(s)/Principal Investigator(s) and NIH Program Official. 
• The existence of clear and concrete go/no-go milestones for transition from the R61 to the R33 phase is a requirement for this NOFO. Applications lacking milestones will be administratively withdrawn without review. Potential applicants with questions about suitable milestones are encouraged to contact NIH program staff prior to application.

Timeline

• Applicants must provide a detailed project timeline which includes the proposed milestones for progression from the R61 phase to the R33 phase. This timeline must include the specific goals of each phase, and applicants must indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones must be clearly delineated and should appear as the last element of the Research Strategy section.

Letters of Support: In addition to the usual letters of support from key personnel and other significant contributors, applicants must also include the following letters of support.

• The application must include a letter of support from a clinical collaborator, as described in Part 2, Section I. This letter of support must outline a collaboration between the preclinical and clinical investigators, which discusses the ways in which the clinical collaborator will advise on model development as it relates to the pathophysiology and/or disease etiology of NeuroHIV clinical populations on cART. This letter should also discuss the feasibility and clinical applicability of selected neurological endpoint measures in preclinical and clinical settings.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply - Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov. 

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this NOFO: 

• How well does the proposed preclinical model recapitulate the current clinical picture of NeuroHIV in human patients on cART?
• How well have the investigators considered the phenotypes and physiology of NeuroHIV in the design and validation of their preclinical model system?
• What is the utility of the proposed NeuroHIV model from both a preclinical and clinical perspective?
• How strong is the rationale of unmet need for the proposed NeuroHIV model?
• How appropriate is the proposed preclinical model for addressing future disease mechanistic and/or translational questions in the context of NeuroHIV in the cART era?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

Specific to this NOFO:

• How knowledgeable and experienced is the investigative team in the interrogation of NeuroHIV basic disease mechanisms?
• How sufficient is the investigative team's expertise in the areas of in vivo or ex vivo preclinical modeling, experimental design, statistical analysis, and neurobiological outcome analysis?
• How strong is the collaboration between preclinical and clinical NeuroHIV experts? What is the evidence (from their letter of support) that the clinical collaborator will play a role in the design and characterization/validation of the proposed NeuroHIV model so that it more accurately represents the current clinical picture of NeuroHIV?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

• How adequate are the plans for generating, optimizing, and validating the proposed NeuroHIV model? Are these described in sufficient detail?
• How appropriate are the selected neurobiological endpoint measures for evaluating the utility of the model and characterizing CNS phenotypes in the context of NeuroHIV in the cART era? Are these described in sufficient detail? 
• How well do the selected neurobiological endpoints demonstrate an understanding of the current clinical picture of NeuroHIV and where the proposed model will fit into the field?
• How feasible is the proposed NeuroHIV model to implement and how broadly applicable will it be to the field?
• How rigorous is the proposed statistical analysis for the experimental design and the quantitative characteristics of selected neurobiological endpoints? Are sample sizes, power analyses, the consideration of biological variables such as sex and age, and other elements of rigorous experimental planning sufficiently demonstrated throughout the approach section and appropriately justified? If using vertebrate animals, is there strong evidence that sufficient animals will be available to conduct rigorous model characterization?
• What is the evidence in the experimental plan that makes a compelling case that the proposed strategy is distinct from and more likely to represent the current clinical picture of NeuroHIV in the cART era than other NeuroHIV preclinical models? 

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones and Timeline

• How robust are the proposed milestones, and how likely is it that they will enable clear and concrete go/no-go decisions at the R61/R33 transition? 
• In what ways will the milestones allow the evaluation of progress in the R61 phase and provide confidence that the investigators will be able to successfully implement the R33 phase?
• How detailed, realistic, and appropriate is the proposed timeline for achieving the milestones and other necessary steps of model generation and phenotyping?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Specific to this NOFO:

Intellectual Property (IP) Considerations

It is not anticipated that new IP will necessarily have to be filed for a preclinical model. However, reviewers will consider whether the IP Plan attachment outlines any known constraints that could impede the model from being disseminated to the NeuroHIV research community (e.g., certain restrictions under transfer or sharing agreements, etc.) and whether these issues are adequately addressed to achieve the overall goals of the program with regard to model dissemination. 

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NINDS, in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Not Applicable

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting.  To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

William Daley, PhD
Telephone: 301-496-1431
Fax: 301-402-2060
Email: william.daley@mail.nih.gov

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

Kathleen Ruth Borgmann
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: (301) 594-6561
E-mail: kathleen.borgmann@nih.gov

Chief, Scientific Review Branch
National Institute for Neurological Disorders and Stroke (NINDS)
Email: nindsreview.nih.gov@mail.nih.gov

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

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

Pamela G Fleming
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.