Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) National Institute on Drug Abuse (NIDA) National Institute of Neurological Disorders and Stroke (NINDS)
Funding Opportunity Title	Eradication of HIV-1 from CNS Reservoirs: Implications for Therapeutics (R21)
Activity Code	R21 Exploratory/Developmental Grant Award
Announcement Type	Reissue of RFA-MH-13-031
Related Notices	August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	RFA-MH-14-171
Companion Funding Opportunity	RFA-MH-14-170, R01 Research Project Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242, 93.853, 93.856, 93.279
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) invites research grant applications to address the problem of HIV-1 persistence focused solely on the central nervous system (CNS) of HIV-infected persons treated with Highly Active Anti-Retroviral Therapy (HAART). This FOA will support innovative research in five areas: (1) basic research to identify and characterize persistent HIV-1 in CNS derived cells such as macrophages, microglia and/or astrocytes in the setting of suppressive anti-retroviral therapy, with or without substance use; (2) basic research to determine the mechanisms involved in the temporal establishment, maintenance, and resurgence of persistent HIV-1 in CNS in relationship to the timing of antiretroviral therapy; (3) development of physiologically relevant animal models and CNS-based cellular assays that recapitulate HIV-1 persistence and latency in the presence of effective HAART, including effects of chronic substance use; (4) assessment of current and emerging eradication approaches on whether and/or how well they have successfully reactivated persistent HIV from CNS-derived cells such as macrophages, microglia and astrocytes; and (5) assessment of CNS toxicity and adverse impact of current and emerging eradication strategies. Applications ranging from basic to translational research in domestic and international settings are of interest. Multidisciplinary research teams are encouraged but not required.

Posted Date	April 10, 2013
Open Date (Earliest Submission Date)	August 17, 2013
Letter of Intent Due Date(s)	August 17, 2013
Application Due Date(s)	September 17, 2013, 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.
AIDS Application Due Date(s)	September 17, 2013, by 5:00 PM local time of applicant organization.
Scientific Merit Review	November 2013
Advisory Council Review	January 2014
Earliest Start Date	April 2014
Expiration Date	September 18, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. 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

Highly Active Anti-Retroviral Therapy (HAART) suppresses HIV-1 RNA levels in plasma and cerebral spinal fluid (CSF), yet it does not completely eliminate the virus. This limitation is due to latent sequestered virus found in cellular and tissue reservoirs. The primary source of resurgent virus is believed to be derived from latently infected resting memory CD4+ T cells, including both central memory, transitional memory as well as some na ve cells. Other potential cellular reservoirs under investigation include monocyte-derived macrophages, microglial cells, and astrocytes. HIV-1 is also sequestered in anatomic reservoirs such as gut-associated lymphoid tissue and brain.

The brain reservoir is a pool of long lived cells primarily astrocytes, perivascular macrophages and microglia that can harbor replication competent virus. Neuropathologic, CSF and clinical studies have shown that low level HIV replication can occur in brain despite undetectable HIV RNA in plasma. HIV DNA has been detected in up to 19% of glial fibrillary acidic protein (GFAP) positive cells and astrocyte infection frequency correlated with the severity of neuropathologic changes and proximity to perivascular macrophages. Studies using the simian immunodeficiency virus (SIV) macaque model of HIV/AIDS and CNS disease, have shown that the levels of brain viral RNA were lowered in response to effective HAART, however viral DNA was unaffected. There is also evidence of compartmentalized viral evolution in the brain suggesting that independent HIV-1 replication can occur in the CNS and these brain variants can potentially reseed the periphery. There may be differences in the mechanisms of latency establishment between the periphery and cells in the brain. For example long terminal repeat (LTR) sequences isolated from the CNS and periphery from the same HIV + individual cluster separately and respond differently to transcriptional activators.

The NIH has placed a high research priority on the goal of eradicating HIV-1 from persistent reservoirs in an effort to find innovative strategies to cure the body of HIV-1 infection. The objective of this funding opportunity is to foster investigations focused solely on CNS HIV-1 latency that will provide the foundation for rapid development of innovative therapeutic interventions to eradicate HIV-1 from the brain. Additional research is needed to specifically target viral reservoirs in the CNS sanctuary because of unique anatomic features in the brain, such as the blood-brain barrier and enclosure within the restricted skull cavity. One of the challenges for eradication of CNS-specific HIV-1 reservoirs includes developing HIV-1 eradication strategies that can penetrate the blood-brain barrier. Another challenge is that the current eradication strategies being tested may have detrimental effects in the CNS, due to neuronal toxicity and inflammatory sequelae resulting from reactivation of the 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.

The goals of this initiative are to define and characterize the sources of HIV persistence in the CNS for people on suppressive HAART, and foster translational research to enable eradication of HIV-1 from the brain.

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

• Identify all potential cellular reservoirs of latent HIV-1 within the CNS (macrophages, microglia, astrocytes, T-cells, etc.);
• Discover the molecular mechanisms involved in establishment, maintenance, and resurgence of CNS-based HIV-1 reservoirs in relationship to the effects and timing of HAART;
• Elucidate how persistently infected cells of the CNS escape the immune response and persist despite HAART;
• Examine the role of CNS inflammation in maintaining HIV persistence within this compartment;
• Develop physiologically relevant CNS-based cell assays that recapitulate; HIV-1 persistence in the presence of effective antiretroviral therapy; latency; and viral resurgence upon removal of HAART;
• Identify assays to quantify level of residual latent and replication-competent virus and residual viral replication in CNS compartment in patients on suppressive anti-retroviral therapy;
• Develop novel neuroimaging approaches to detect latent infection within the CNS;
• Determine new cellular markers that identify latently infected cells in the CNS;
• Develop high throughput assays or refine physiologically relevant primary cells for use in identifying drug candidates for eradication of HIV-1 in the brain;
• Adapt or refine existing animal models to study CNS HIV-1 persistence or for testing virus eradication strategies;
• Assess current HIV-1 eradication strategies for CNS toxicity, neuroinflammation, and neurocognitive outcomes;
• Develop novel eradication strategies with improved penetration through blood-brain barrier to target and eliminate latent CNS reservoirs (gene therapy, nanotechnology, zinc finger technology);
• Identify novel strategies to prevent viral resurgence in the CNS upon cessation of HAART.

In addition to research topics identified above NIDA has defined other areas of emphasis since emerging evidence suggests that substance use can affect HIV pathogenesis, including in the brain. It has been demonstrated that exposure to certain abused substances reactivate latent HIV infection, including in human brain-derived microglial cells. Given that chronic exposure to injection or non-injection substances of abuse generally precedes HIV-1 infection, it is important to understand how particular patterns or combinations of substance use affect CNS susceptibility to HIV-1 infection, maintenance of latent or persistent infection within the CNS compartment, mechanisms of HIV-1 reactivation, and treatment strategies for eradication

NIDA encourages novel approaches to address the CNS reservoir in the context of specific, well-characterized patterns or models of substance use, abuse, or addiction (such as heroin/narcotics, psychostimulants including cocaine or methamphetamine, nicotine, marijuana, prescription drugs, or polysubstance use). NIDA does not support research on alcohol unless the focus is on polysubstance use. A key consideration for applicants is that, in general, chronic exposure to substances of abuse precedes HIV-1 infection, and applicants are strongly encouraged to incorporate chronic use behavioral paradigms in their research applications. Approaches may include in vitro, ex vivo, and/or in vivo studies, and may focus on specific neural circuits or signaling pathways highly relevant to substance use, abuse, or addiction (such as dopamine, serotonin, norepinephrine, GABA, opioid, nicotinic, or cannabinoid signaling). Examples of research topics of interest appropriate for NIDA include but are not limited to:

• Mechanisms of substance use impact on molecular regulation of HIV integration and expression in specific brain-derived cell populations (e.g., astrocytes, microglia) and/or in specific brain regions by chronic substance use;
• Substance use effects on viral and host DNA, RNA, and protein modifications that impact HIV expression and reactivation in the CNS compartment;
• Epigenomic, non-coding RNA (including microRNA), or transcriptional regulatory processes modified by HIV and substance use that impact latent or persistent HIV infection in the CNS;
• Substance use and relevant receptor signaling pathways involved in maintenance of latent or persistent HIV infection and subsequent neuropathogenesis;
• Interaction of substance use and relevant signaling pathways with CNS inflammatory responses in the absence or presence of treatment agents, and the impact on maintenance of HIV persistence within this compartment;
• Changes in regulation of brain energy utilization that impact HIV in the CNS reservoir with chronic exposure to substance use;
• Investigations into the role of exosomes in CNS processes relevant to both substance abuse and the establishment of HIV latency;
• Enhanced or diminished efficacy of small molecule or other eradication agents in the context of substance use, including evaluation of pharmacologic, pharmacokinetic, or pharmacogenomic interactions;
• Effects of other infections, such as HCV, on CNS HIV reservoirs in substance abusers.

Applications responsive to this FOA are expected to include data sharing plans, incorporating data dictionaries, current definitions, and careful documentation. It is a major objective of this FOA to establish and promote the use of data sharing with the wider community. As such, it is expected that applications will include information on the type and descriptors of data to be shared, as well as a plan for data coordination, standardization, access privileges, timeline for release of data, and location of data to be shared post-award, consistent with achieving the goals of the program.

Highly innovative and novel hypotheses are encouraged to focus solely on HIV-1 latency in the CNS. Applicants are encouraged to state clearly and concisely what makes the application unusually innovative or unconventional. For example, state how the hypothesis creates a novel paradigm, or challenges a standard paradigm, or how the hypothesis integrates diverse sources of information, develops novel approaches, or differs from what other investigators have attempted. If the approach entails a high degree of risk, then clearly state how the benefits and rewards might outweigh the risks.

The National NeuroAIDS Tissue Consortium (NNTC) is a resource of high quality tissue (CNS, PNS, etc.) and fluid specimens (CSF, blood, etc.) from patients who have died with HIV-1. The NNTC is also a potential source of primary cells which may prove useful in the design of screening assays. The use of resources from large NIH-funded HIV-1 related studies such as Multi-Center AIDS Cohort Study (MACS), Women s Interagency HIV Study (WIHS), CNS HIV Antiretroviral Therapy Effects Research (CHARTER), and the HIV Brain Sequence Database (HIVBrainSeqDB) is encouraged.

The NINDS does not support applications in response to this FOA that involve human subjects.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission of unfunded applications submitted in response to RFA-MH-13-031 The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIMH intends to commit approximately $1,500,000 in FY 2014 to fund 3-5 awards in response to this FOA and companion R01 FOA. Future year amounts will depend on annual appropriations. NIDA intends to commit approximately $2,000,000 in FY2014 to fund 4-6 awards in response to this FOA and companion R01 FOA. NINDS intends to commit approximately $1,500,000 in FY 2014 to fund 3-5 awards in response to this FOA and the companion R01 FOA.
Award Budget	Direct costs are limited to $275,000 over an R21 two-year period, with no more than $200,000 in direct costs allowed in any single year. Consortia F&A costs are not included in the direct cost limit.
Award Project Period	The total project period for an application submitted in response to this FOA may not exceed two years.

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

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)

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)
• 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 (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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 SF 424 (R&R) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 DUNS number and 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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 SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Jeymohan Joseph, Ph.D.
Division of AIDS Research
National Institute on Mental Health
6001 Executive Boulevard, Room 6110, MSC 9619
Bethesda, MD 20892-9619
Rockville, MD 20852 (for express/courier service)
Telephone: 240-627-3869
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan, incorporating data dictionaries, current definitions, and careful documentation. Applications should include information on the type and descriptors of data to be shared, as well as a plan for data coordination, standardization, access privileges, timeline for release of data, and location of data to be shared post-award, consistent with achieving the goals of the program.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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 SF424 (R&R) Application Guide.

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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) 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 Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. 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 FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NIMH Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

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).

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? 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? Does the project have the potential to lead to increases in our knowledge base of HIV persistence, latency, or reactivation of HIV-1 upon removal of HAART?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

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? If successful will this application provide the foundation for rapid development of innovative therapeutic interventions to eradicate HIV-1 from the brain?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? Has the investigator discussed how the benefits of the highly innovative application might outweigh the risks of the approach?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

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?

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.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six 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 six 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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal 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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

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.

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 following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the Center for Scientific Review, in accordance with NIH peer review policy and procedures, 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:

• 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.
• Will receive a written critique.

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

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 FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council l. 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.
• Compliance with resource sharing policies.

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.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

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.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. 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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Phone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

Jeymohan Joseph, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-6100
Email: [email protected]

Vishnudutt Purohit, DVM, Ph.D.
Program Director
Chemistry and Physiological Systems Research Branch
Division of Basic Neuroscience & Behavioral Research
National Institute on Drug Abuse (NIDA), NIH, DHHS
Telephone: 301-594-5753
Fax: 301-594-6043
Email: [email protected]

May Wong, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1431
Email: [email protected]

Robert Freund, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1050
Email: [email protected]

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: [email protected]

Carol Alderson
National Institute on Drug Abuse (NIDA)
Telephone: 301-933-6196
Email: [email protected]

Ms. Tijuanna DeCoster
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9531
Email: [email protected]

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 45 CFR Parts 74 and 92.