VIRAL GENETICS IN HIV/CNS DISEASE: IMPLICATIONS FOR PATHOGENESIS
RELEASE DATE: March 29, 2002
RFA: RFA-MH-02-012
National Institute of Mental Health (NIMH)
(http://www.nimh.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov)
National Institute on Drug Abuse (NIDA)
(http://www.nida.nih.gov)
LETTER OF INTENT RECEIPT DATE: May 15, 2002
APPLICATION RECEIPT DATE: June 12, 2002
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The National Institute of Mental Health (NIMH), the National Institute of
Neurological Disorders and Stroke (NINDS), and the National Institute on Drug
Abuse (NIDA) solicit applications for grants to support studies focused on
understanding the molecular and viral genetic factors controlling HIV-1
neuropathogenesis in the setting of highly active anti-retroviral therapy
(HAART). The objective of this cooperative effort is to foster
investigations utilizing genetic approaches to study mechanisms of HIV-1
induced nervous system disease with emphasis on trafficking, cell type
specific and regional compartmentalization, viral evolution, functional
diversity, establishment of latent reservoirs and the emergence of drug
resistance in the central nervous system (CNS) versus other body
compartments.
RESEARCH OBJECTIVES
Background
HIV enters the nervous system soon after infection, eventually resulting in a
range of mild to severe cognitive, motor and behavioral symptoms. The most
severe cognitive impairments have been described from a clinical diagnosis as
HIV-associated dementia (HAD). Currently available HAART therapy has reduced
the severity of neurological and neurobehavioral dysfunction in infected
individuals. However, the drugs used for HAART therapy do not enter the
brain efficiently. This presents unique challenges in controlling HIV-1
infection, spread and persistence in the CNS compartment. The dynamics of
viral responses in the CNS in terms of trafficking, compartmentalization,
viral evolution, emergence of drug resistance and establishment of viral
reservoirs in the setting of HAART is not completely understood. In order to
assess the potential long-term implications of HAART on neurological disease
it is critical to have a thorough understanding of the molecular and viral
genetic factors controlling neuropathogenesis.
The goal of this initiative is to encourage research using genetic approaches
to improve our understanding of HIV-induced nervous system disease in the
presence or absence of HAART treatment. The following are examples of
research that are encouraged under this RFA.
I. Viral Evolution in the CNS.
a. Determine if unique viral sequences are associated with neurovirulence
b. Study of the role of viral evolution and trafficking in the establishment
of regional genetic heterogeneity of HIV-1 in CNS
c. Comparisons of sequences of HIV-strains derived from CNS and other organs
for assessment of compartmentalized virus evolution
II. CNS Cell type Specific Compartmentalization of HIV Infection.
a. Identification and sequence analysis of unique receptors used to infect
perivascular and parenchymal macrophages, microglia, endothelial cells and
astrocytes
b. Assessment of viral sequences that are important in infection and
replication in various CNS derived cells (macrophages, microglia, endothelial
cells and astrocytes)
c. Identification of CD4-independent variants in brain and potential
implications in neuropathogenesis
III. HIV-1 Molecular Diversity and Resulting Functional Consequences.
a. Assessment of molecular diversity of various HIV-1 genes (e.g., Tat, Nef)
and resultant functional consequences in CNS
b. Correlation of molecular changes of HIV-1 strains derived from demented
and non-demented individuals and associated impact on function
c. Study of the role of defective/non-infectious envelope in the induction
of neurotoxicity as well as in stimulating release of toxic mediators
d. Comparisons of the ability of various CNS and non-CNS derived HIV-1
strains to release neurotoxins from glial cells and macrophages and
assessment of the relationship, if any, to viral sequences and neurovirulence
e. Assessment of differences between HIV-1 envelopes in signaling of
macrophages, microglial cells, astrocytes, endothelial cells, and neurons,
identification of any relationships between signaling differences, HIV-1
envelope sequence diversity and functional effects.
IV. Emergence of Drug Resistance in CNS parenchyma/CSF versus other body
compartments.
a. Assessment of independent emergence of drug resistance mutations in CNS
parenchyma/CSF versus other body compartments
b. Sequence analysis of HIV-1 derived from patient populations with
discordant control of HIV-1 in CSF and plasma to assess emergence of
compartmentalized drug resistance as well as potential reseeding of
peripheral compartments
V. Use of novel molecular approaches to facilitate studies of HIV induced
neuropathogenesis. The heteroduplex-tracking assay is an example of an assay
that provides advantages in sampling of HIV populations from various
compartments.
VI. Studies focusing on the involvement of opiod/cannabinoid systems in the
above processes are appropriate.
The research examples described above are illustrative and are not meant to
be all inclusive. Although research with HIV-1 is the focus of this
initiative, studies with animal models such as those using SIV and FIV are
also strongly encouraged.
MECHANISM OF SUPPORT
This RFA will use NIH research project grants (R01) award mechanism. As an
applicant you will be solely responsible for planning, directing, and
executing the proposed project. This RFA is a one-time solicitation. Future
unsolicited, competing-continuation applications based on this project will
compete with all investigator-initiated applications and will be reviewed
according to the customary peer review procedures. The anticipated award
date is December 1, 2002.
This RFA uses just-in-time concepts. It also uses the modular and non-
modular budgeting formats. (see
https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if
you are submitting an application with direct costs in each year of $250,000
or less, use the modular format.
FUNDS AVAILABLE
NIMH intends to commit approximately $1,200,000 in FY 2003 to fund three to
five new and/or competitive continuation grants in response to this RFA.
NINDS will commit $800,000 in FY 2003 to fund two or three new grants that
are responsive to this initiative. NIDA plans to fund two or more grants
supporting meritoriously applicable research in this area. An applicant may
request a project period of up to five years. Because the nature and scope
of the proposed research will vary from application to application, it is
anticipated that the size and duration of each award will also vary.
Although the financial plans of the IC(s) provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds and
the receipt of a sufficient number of meritorious applications.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution 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 programs.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:
o Direct your questions about scientific/research issues to:
Jeymohan Joseph, Ph.D.
Center for Mental Health Research on AIDS
National Institute on Mental Health
6001 Executive Boulevard, Room 6202, MSC 9619
Bethesda, MD 20892-9619
Telephone: (301) 443-6100
FAX: (301) 443-9719
Email: jjeymoha@mail.nih.gov
Toby Behar, Ph.D.
Neural Environment Cluster
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Rm 2114A, MSC 9521
Bethesda, MD 20892-9521
Telephone: (301) 496-1431
FAX: (301) 480-2424
Email: behart@ninds.nih.gov
Charles Sharp, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 443-1887
FAX: (301) 594-6043
Email: cs107m@nih.gov
o Direct your questions about peer review issues to:
Michael Kozak, Ph.D.
Chief, Extramural Review Branch
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9608
Bethesda, MD 20892-9608
Telephone: (301) 443-1340
FAX: (301) 594-0702
Email: mkozak@mail.nih.gov
o Direct your questions about financial or grants management matters to:
Brian Albertini
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-0004
FAX: (301) 443-0219
Email: albertinib2@mail.nih.gov
Diana Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3290, MSC 9537
Bethesda, MD 20892-9537
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: dj35j@nih.gov
Gary P. Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD 20892-9541
Telephone: (301) 443-6710
FAX: (301) 594-849
Email: gf6s@nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes
the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
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.
The letter of intent is to be sent by the date listed at the beginning of
this document. The letter of intent should be sent to:
Jeymohan Joseph, Ph.D.
Center for Mental Health Research on AIDS
National Institute on Mental Health
6001 Executive Boulevard, Room 6202, MSC 9619
Bethesda, MD 20892-9619
Telephone: (301)443-6100
FAX: (301)443-9719
Email: jjeymoha@mail.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications
requesting up to $250,000 per year in direct costs must be submitted in a
modular grant format. The modular grant format simplifies the preparation of
the budget in these applications by limiting the level of budgetary detail.
Applicants request direct costs in $25,000 modules. Section C of the
research grant application instructions for the PHS 398 (rev. 5/2001) at
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step
guidance for preparing modular grants. Additional information on modular
grants is available at
https://grants.nih.gov/grants/funding/modular/modular.htm.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001)
application form must be affixed to the bottom of the face page of the
application. Type the RFA number on the label. Failure to use this label
could result in delayed processing of the application such that it may not
reach the review committee in time for review. In addition, the RFA title
and number must be typed on line 2 of the face page of the application form
and the YES box must be marked. The RFA label is also available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of
the application, including the Checklist, and three signed, photocopies, in
one package to:
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application must be
sent to:
Jean G. Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD 20892-9609
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 443-3367
Email: jnoronha@mail.nih.gov
APPLICATION PROCESSING: Applications must be received by the application
receipt date listed in the heading of this RFA. If an application is
received after that date, it will be returned to the applicant without
review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The
CSR will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must
include an Introduction addressing the previous critique.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the participating ICs. Incomplete and/or non-responsive
applications will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated
for scientific and technical merit by an appropriate peer review group
convened by the NIMH in accordance with the review criteria stated below. As
part of the initial merit review, all applications will:
o Receive a written critique
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications under
review, will be discussed and assigned a priority score
o Receive a second level review by the National Advisory Councils of the
participating institutes.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewers will be asked to discuss the following
aspects of your application in order to judge the likelihood that the
proposed research will have a substantial impact on the pursuit of these
goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria
in assigning your application"s overall score, weighting them as appropriate
for each application. Your application does not need to be strong in all
categories to be judged likely to have major scientific impact and thus
deserve a high priority score. For example, you may propose to carry out
important work that by its nature is not innovative but is essential to move
a field forward.
(1) SIGNIFICANCE: Does your study address an important problem? If the aims
of your application are achieved, how do they advance scientific knowledge?
What will be the effect of these studies on the concepts or methods that
drive this field?
(2) APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Do you acknowledge potential problem areas and consider alternative
tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project challenge
existing paradigms or develop new methodologies or technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out
this work? Is the work proposed appropriate to your experience level as the
principal investigator and to that of other researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional
support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will also be reviewed with respect to the following:
o PROTECTIONS: The adequacy of the proposed protection for humans, animals,
or the environment, to the extent they may be adversely affected by the
project proposed in the application.
o INCLUSION: The adequacy of plans to include subjects from both genders,
all racial and ethnic groups (and subgroups), and children as appropriate for
the scientific goals of the research. Plans for the recruitment and
retention of subjects will also be evaluated. (See Inclusion Criteria
included in the section on Federal Citations, below)
o DATA SHARING: The adequacy of the proposed plan to share data.
o BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: May 15, 2002
Application Receipt Date: June 12, 2002
Peer Review Date: July/August 2002
Council Review: October 2002
Earliest Anticipated Start Date: December 1, 2002
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for
assessment of patient eligibility and status, rigorous data management,
quality assurance, and auditing procedures. In addition, it is NIH policy
that all clinical trials require data and safety monitoring, with the method
and degree of monitoring being commensurate with the risks (NIH Policy for
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12,
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of
the NIH that women and members of minority groups and their sub-populations
must be included in all NIH-supported clinical research projects unless a
clear and compelling justification is provided indicating that inclusion is
inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research - Amended, October, 2001," published in the NIH Guide for Grants and
Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are
available at
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research, updated racial and ethnic categories in compliance with the new OMB
standards, clarification of language governing NIH-defined Phase III clinical
trials consistent with the new PHS Form 398, and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a)
all applications or proposals and/or protocols must provide a description of
plans to conduct analyses, as appropriate, to address differences by
sex/gender and/or racial/ethnic groups, including subgroups if applicable,
and b) investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
The NIH maintains a policy that children (i.e., individuals under the age of
21) must be included in all human subjects research, conducted or supported
by the NIH, unless there are scientific and ethical reasons not to include
them. This policy applies to all initial (Type 1) applications submitted for
receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the inclusion of children as participants in
research involving human subjects that is available at
https://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research
on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).
It is the responsibility of the applicant to provide the official NIH
identifier(s)for the hESC line(s)to be used in the proposed research.
Applications that do not provide this information will be returned without
review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2)
cited publicly and officially by a Federal agency in support of an action
that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope
of this amendment. NIH has provided guidance at
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the
application. In addition, applicants should think about how to structure
informed consent statements and other human subjects procedures given the
potential for wider use of data collected under this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals
for NIH funding must be self-contained within specified page limitations.
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs)
should not be used to provide information necessary to the review because
reviewers are under no obligation to view the Internet sites. Furthermore,
we caution reviewers that their anonymity may be compromised when they
directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of "Healthy
People 2010," a PHS-led national activity for setting priority areas. This
RFA is related to one or more of the priority areas. Potential applicants
may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance Nos. 93.242 (NIMH), 93.853 (NINDS), and 93.279
(NIDA), and is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review. Awards are made under
authorization of Sections 301 and 405 of the Public Health Service Act as
amended (42 USC 241 and 284) and administered under NIH grants policies
described at https://grants.nih.gov/grants/policy/policy.htm and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and discourage the use of all tobacco products. In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in
certain facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care, or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.