Expired PA-14-095: Eradication of HIV-1 from Central Nervous System Reservoirs (R01)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) National Institute of Allergy and Infectious Diseases (NIAID) National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Eradication of HIV-1 from Central Nervous System Reservoirs (R01)
Activity Code	R01 Research Project Grant
Announcement Type	New
Related Notices	December 13, 2016 - This PAR has been re-issued as PA-17-084. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PA-14-095
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242, 93.279, 93.856, 93.853, 93.855
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 the 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 impacts 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.

Key Dates

Posted Date	February 11, 2014
Open Date (Earliest Submission Date)	April 7, 2014
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard AIDS dates apply, 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)	Standard AIDS dates apply 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.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	New Date December 13, 2016 per issuance of PA-17-084. (Original Expiration Date: January 8, 2017 )
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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

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 the 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 the 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 NIMH, NIAID and NINDS 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 virus. Therefore, there is a need for discovery research focused solely on expanding our knowledge base of CNS HIV-1 latency and eradication strategies tailored directly for the brain compartment. These may also include approaches to target latent CNS infection using viral silencing approaches rather than reactivation strategies.

NIDA has placed a priority on studying the impact of chronic substance abuse on latent HIV eradication within CNS cell types. Drugs of abuse can modulate CNS infections and HIV levels within the brain. For example, cocaine, methamphetamine, and nicotine are capable of increasing blood brain permeability which may promote increased migration of monocytes from the periphery to the brain where they can be infected with HIV released from the HIV-infected perivascular macrophages and microglia and this may increase the brain pool of HIV reservoirs. Most of drugs of abuse, especially cocaine and methamphetamine, are known to increase brain levels of dopamine which has been shown to promote HIV replication in macrophages. Thus drugs of abuse may add to the pool of brain HIV reservoirs by increasing brain dopamine levels. In addition, metabolism of dopamine results in the release of free radicals that have potential of inducing the release of inflammatory mediators (e.g. TNF-alpha) which can activate NF-kB (Nuclear factor kappa B), which is a key HIV transcription factor. Furthermore, cocaine and methamphetamine have been shown to activate NF-kB and induce HIV-LTR activation in macrophages/microglia. Exposure of these drugs to human subjects maintained on HAART may reactivate latent HIV in brain macrophages/microglia with adverse consequences in the absence of effective HIV eradication strategies.

The goals of this initiative are to define and characterize the sources of HIV persistence in the CNS for people on suppressive HAART with and without substance abuse, and foster translational research to enable eradication of HIV-1 from the brain.

Research Objectives and Scope

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 (e.g. gene therapy, nanotechnology, zinc finger technology);
Identify novel strategies to prevent viral resurgence in the CNS upon cessation of HAART;
Develop innovative strategies to selectively identify and eliminate latently infected cells without reactivation of provirus;
Identify novel approaches for viral silencing including siRNA targeting;
Develop unique class of HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia;

Applications submitted 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.

Leverage Existing Government Resources

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 use of other resources from large NIH-funded HIV-1 related studies is encouraged such as the Multi-Center AIDS Cohort Study (MACS), Women s Interagency HIV Study (WIHS), CNS HIV Antiretroviral Therapy Effects Research as a Resource (CHARTER as a Resource), HIV Brain Sequence Database (HIVBrainSeqDB), and the AIDS Clinical Trials Group (ACTG).

Section II. Award Information

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 Renewal Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period	The maximum period of 5 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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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)

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.

Required Registrations

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.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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.

Section IV. Application and Submission Information

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

Page Limitations

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

Required and Optional Components

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.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover