Expired PA-14-094: HIV Infection of the Central Nervous System (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 on Alcohol Abuse and Alcoholism (NIAAA) National Institute of Allergy and Infectious Diseases (NIAID) National Institute on Drug Abuse (NIDA) National Institute of Neurological Disorders and Stroke (NINDS)
Funding Opportunity Title	HIV Infection of the Central Nervous System (R01)
Activity Code	R01 Research Project Grant
Announcement Type	Reissue of PA-11-014
Related Notices	January 05, 2017 - This PA has been reissued as PA-17-100. 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-14-094
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, 93.273, 93.279, 93.853, 93.856, 93.855
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) invites research grant applications focused on defining the pathogenic mechanisms involved in Human Immunodeficiency Virus (HIV)-1 Associated Neurocognitive Disorders (HAND) and, identifying therapeutic strategies to treat and prevent the neurobehavioral and neurological effects of HIV-1 on the central nervous system (CNS). Basic and translational research in domestic and international settings are of interest. Multidisciplinary research teams and collaborative alliances 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	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

The prevalence of Human Immunodeficiency Virus (HIV)-1 Associated Neurocognitive Disorders (HAND) remains high despite widespread use of antiretroviral therapy. For example the CHARTER project (CNS HIV Anti-Retroviral Effects Research), which is a large epidemiologic study conducted in the United States, examined 1,574 participants cross-sectionally and 657 participants longitudinally reported a HAND prevalence rate of 47% in HIV infected individuals. The phenotype of neurologic and neurocognitive complications are also evolving in the era of highly active antiretroviral therapy (HAART). In an effort to accurately classify observed phenotypic changes, a revised American Academy of Neurology definitional criteria for HAND was adopted. The categories of HAND include Asymptomatic Neurocognitive Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD). In the current treatment environment, MND is most prevalent, yet recent studies demonstrate that even mild neurocognitive deficits can interfere with activities of daily living and reduce quality of life in long-standing aviremic HIV-positive patients. These clinical data inform the need for further research aimed at improving or preserving neurocognitive function in the presence of long term antiretroviral therapy.

Extensive research is ongoing to understand the molecular mechanisms of HIV neuropathogenesis. HIV-1 infected macrophages and microglia appear to contribute to neurological injury through release of various factors, including viral gene products, cytokines and chemokines. Neuronal loss, detected at autopsy in HIV-infected patients, is thought to occur through bystander effects, reactive oxygen species-mediated damage to cells and, likely results from apoptosis. Morphologic studies demonstrate synaptodendritic degenerative changes with significant loss of synapses, decreased numbers of dendritic branches, and retraction of dendritic spines. While much has been learned in the last two decades regarding the pathogenic processes involved in HIV-associated CNS disease, there are several gap areas related to the functional implications of these neurological changes and the novel pathophysiological mechanisms driving HAND in the HAART era. Despite excellent viral control in the CNS, low level replication in specific brain regions, chronic inflammation, and changes in brain anatomy and homeostasis are likely to play pivotal roles in the expression of HAND. Exosomes also could play a critical role in modulating inflammation, neurodegeneration and gene expression that could impact on HAND.

Viral genetic variation impacts HIV neuropathogenesis by altering neurovirulence, neurotropism, cell type specific and regional compartmentalization, CNS trafficking, and discordant viral evolution in the brain. Geographic genetic variation in viral clades may also play a role in HIV neuropathogenesis and disease outcomes. In addition, variants in several host genetic factors have been reported to impact the pathophysiology of HAND. Given that both viral and host genetic contributions have advanced our understanding of HAND, new genetic technologies may complement this effort, provide unique perspectives on the neuropathology, and aid in the identification of innovative strategies for the discovery of therapeutic drug targets to prevent, or interfere with, progression of HAND. The use of state-of-the-art genetic approaches (including transcriptomics, phenomics, epigenomics, single genome sequencing, whole genome association studies, ultra-deep sequencing, exome sequencing, and systems biology) as well as the use of human sample resources and animal model systems are encouraged to study, and validate, viral and host genetic contributions to HIV neuropathogenesis.

Another critical issue that is of emerging interest is the interaction of chronic HIV infection, living with HAART long term, and aging associated neurodegenerative processes. The Center for Disease Control has indicated that the number of persons aged 50 years and older living with HIV/AIDS is increasing and derives from two subpopulations: (1) HIV-diagnosed cases of a younger group surviving into older age because of the efficacy of HAART in reducing mortality; and (2) newly HIV-infected cases of an older group. As a result of this major demographic shift there is an urgent need to better define the underlying pathophysiology of neurological complications and neurocognitive decline in the HIV infected aging populations.

Another key area of focus of this initiative is to develop therapeutic strategies for HAND. These therapeutic strategies include the development of optimal antiretroviral therapies. It is worth noting that there is controversy in the field as to the importance of generating better CNS penetrating antiretrovirals. Recent studies reveal the possible neurocognitive benefits of high central nervous system penetration effectiveness (CPE) ranking regimens and treatment initiation at CD4 counts more than 350/uL. However there is also evidence of the neurotoxic effects of antiretroviral therapy. In addition to less toxic anti-viral approaches, novel therapeutics including immunomodulatory or neuroprotective strategies need to be identified and developed to address the chronic inflammation and neurobiological changes that are central features of this disease.

Eradication of HIV from CNS Reservoirs has now emerged as a major priority area. The brain reservoir is a pool of long lived cells primarily astrocytes, perivascular macrophages and microglia that can harbor replication competent virus. 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. There is a need for 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. Please refer to PA-14-095- Eradication of HIV-1 from the Central Nervous System Reservoirs that provides more details on the types of research areas that are of interest relating to HIV CNS eradication.

Chronic exposure to drugs of abuse, as well as co-infections and co-morbidities that are prevalent in drug using populations, present unique challenges for HIV prevention and treatment and are likely to affect host-virus interaction and disease progression, particularly in the brain and the immune system. The role of drug abuse in fueling the HIV/AIDS epidemic has evolved. While the number of new infections associated with injection drug use has decreased, there is a need to understand how non-injection substance abuse impacts different aspects of infection and disease progression. While it is difficult to separate effects of substance abuse on antiretroviral treatment adherence from direct biological effects, experimental evidence suggests that substances such as methamphetamine, cocaine, opioids and cannabinoids may impact HIV infection, replication, and CNS disease progression. Innate and adaptive immune responses, blood-brain barrier integrity, and CNS homeostasis can be affected by substance abuse as well as withdrawal, and these changes have the capacity to affect HIV-associated disease progression in the CNS, particularly as patients are living longer. More research is needed to elucidate the biological interactions between chronic exposure to drugs of abuse, as well as the neurotransmitter systems and physiological changes involved in addiction, with HIV infection of the CNS and HAND. Studies that address these interactions and define causal relationships with the behavioral and cognitive deficits are of interest.

In summary, the goals of this FOA are to stimulate further research on delineating the pathophysiology of HAND in the setting of long-term HAART and identify potential targets for novel therapeutic strategies in domestic and international settings. Applications ranging from basic research to clinical diagnosis and treatment are of interest. Multidisciplinary research teams and collaborative alliances are encouraged, but not required.

Areas of Research Interest

The research areas that are pertinent to this FOA include, but are not limited to:

Evolving Mechanisms of HIV Neuropathogenesis in the HAART era

Study the impact of low level viral replication and immune activation (in CNS compartment) on HIV neuropathogenesis in the setting of high CD4 counts in the periphery;
Study the role of adaptive and innate immunity in regulating anti-viral responses in the CNS compartment, and the effects of substance abuse on this regulation;
Define the mechanisms regulating fluctuating patterns of CNS symptomatology in the HAART era;
Identify novel molecular markers linked with milder and chronic forms of HIV-associated CNS disease using state-of-the art techniques including genomics, proteomics, metabolomics, systems biology and neuroimaging; Evaluate the molecular mechanisms regulating entry of HIV into the central nervous system (CNS) compartment through the blood-brain barrier;
Define novel pathways leading to neuronal toxicity in the HAART era. These could include autophagy, novel inflammatory mediators, viral factors, excitotoxicity and signaling pathways;
Define the pathways and mechanisms leading to synaptodendritic degenerative changes in the setting of chronic HIV infection, and the protective vs. pathogenic effects of those changes;
Study mechanisms involved in CNS manifestations of HIV-associated immune reconstitution inflammatory syndromes;
Study changes in neuronal excitability, synaptic plasticity, and neural circuit activity that contribute to the development of HAND;
Determine the impact of drugs of abuse, or related receptor signaling pathways or circuits, on the cellular and molecular mechanisms underlying HAND, including HIV trafficking to the CNS, neuron-glial communication, neurophysiologic changes and excitability, neuroplasticity, regional differences in HIV replication or host responses within brain, and blood-brain barrier function;
Investigate the interacting effects of drugs of abuse and HIV proteins on neuronal injury mediated through dopamine and other neurotransmitters; and
Study the impact of drugs of abuse on HIV replication in the brain cells through modulation of anti-HIV microRNA expression.

Exosomes and HIV Neuropathogenesis

Assess the mechanisms of exosome release in CNS derived cells in the setting of HIV infection in vivo/in vitro;
Define exosomal cargo (inflammatory mediators, viral proteins) derived from HIV infected cells and its potential impact on neuronal apoptosis;
Study gene regulation in CNS cells following exposure to exosomes released from HIV infected cells;
Evaluate the potential role of exosomes as biomarkers for HAND progression and response to therapy; and
Determine the utility of exosomes as delivery vehicles for CNS targeted therapeutics.

HIV Neuropathogenesis during Acute and Early Stages of Infection

Identify molecular and cellular mechanisms underlying neurological impairment in acute and early infection in subjects who are not on therapy;
Assess HIV CNS compartmentalization in acute and early stages of infection; and
Evaluate the impact on early initiation of treatment and resulting immune recovery on long term neurologic and neurocognitive outcome, and how factors such as substance abuse affect this relationship.

Viral and Host Genetics

Study the role of viral genetic and epigenetic factors in the pathophysiology of HAND. Understand the role of viral and host transcriptional regulation (including viral protein modifications, histone modifications, changes in chromatin structure, and non-coding RNA) in HIV neuropathogenesis, and the interaction of environmental factors including substance abuse with these regulatory processes;
Conduct viral genetic or host epigenetic studies relating to the establishment and maintenance of CNS latency and reservoirs;
Study the molecular diversity of various HIV-1 genes (e.g., Tat, Nef, Vpr) and resultant functional consequences in the CNS;
Identify the relationships between signaling differences, genetic diversity of HIV proteins and functional effects;
Determine the molecular and genetic mechanisms of HIV clade differences in HIV neuropathogenesis;
Determine the role of host genetic including epigenetic factors in regulating susceptibility to HAND;
Assess the epigenetic host response to viral infection mediated through chromatin modification, non coding RNAs and DNA methylation;
Identify host genetic factors regulating responsiveness to anti-retroviral therapy and neuroprotective adjuvant therapies (pharmacogenomics), and the impact of substance abuse or other environmental factors on these relationships;
Delineate the genetic basis of host restriction factors and the maintenance of viral reservoirs in CNS cell types; and
Identify viral and host genetic biomarkers.

Neuroimaging Studies

Use of neuroimaging approaches such as magnetic resonance spectroscopy (MRS), positron emission tomography (PET), magnetic resonance imaging (MRI), functional MRI (fMRI), blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI), diffusion tensor imaging (DTI), arterial spin-labeling MRI (ASL-MRI) and chemical shift imaging to:

Delineate key biological markers that correlate with disease symptoms, progression, and clinically relevant information regarding cognitive, emotional, neurological, and behavioral performance;
Establish relationships between markers identified by neuroimaging and histopathologic markers of neuronal health and inflammation;
Study the role of unique inflammation-related markers identified by neuroimaging in the pathophysiology of HAND; and
Study the impact on the brain of co-occurring HIV infection and exposure to psychoactive agents.

Aging, Co-morbidities, Co-infections and HAND

Determine the mechanism of HIV neuropathogenesis in older adults;
Assess reciprocal interaction between HIV-associated CNS disease and aging associated neurodegenerative processes as seen in Alzheimer's and Parkinson's Disease;
Evaluate impact of HAND on biomarkers of aging associated neurodegenerative disease such as amyloid, Abeta42, APOE, tau and phospho-tau.
Assess the impact of metabolic changes relating to HAART on neurocognitive outcomes among HIV-1 infected patients. These include studies on the effect of insulin resistance, lipid abnormalities and mitochondrial dysfunction on HIV-associated CNS disease;
Assess other non-infectious co-morbidities (stroke, epilepsy) associated with HAND; and
Assess impact and study mechanisms of hepatitis C co-infection on neurocognitive outcome.

Therapeutics

Develop antiviral therapeutic drugs capable of penetrating the blood-brain barrier and decreasing the viral load in the CNS;
Research mechanisms of HIV persistence within the CNS and development of strategies or drug therapies to eliminate CNS reservoirs;
Identify adjunctive therapies for the treatment of HAND; including neuroprotective strategies and strategies for reducing CNS inflammation, cellular activation, and neurodegeneration;
Develop therapeutic strategies for increasing the effective concentration, or activity, or entry of HAART and other agents into the CNS;
Ascertain the impact of long term HAART on CNS toxicity;
Design strategies to prevent HAND; and
Assess the impact of substance use on effectiveness, or host/viral responses to combination antiretroviral therapy, or other CNS-specific strategies to prevent or treat HAND.

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.

Animal Models and Specimen Resources

The use of animal models (non-human primates, transgenic mice/rats) is encouraged;
Develop novel in vitro, ex vivo or in vivo models for research on HAND Model systems that address the impact of chronic substance use on neuroinflammatory, neurophysiological, neurocognitive or neurobehavioral consequences of CNS HIV infection would be appropriate; and
The use of human specimen resources from large NIH-funded HIV related studies is also encouraged, including, but not limited to:
- 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);
- AIDS Clinical Trials Group (ACTG); and the
- National NeuroAIDS Tissue Consortium (NNTC).

The NIAAA encourages applications that are relevant to the mission of the institute, such as investigations of the co-morbid effects of alcohol use and abuse on mechanisms of HIV infection of the CNS.

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 is 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