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 
http://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 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
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 
http://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 
http://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: 
http://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: http://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 (http://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 
available at 
http://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 
http://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 
http://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 http://grants.nih.gov/grants/stem_cells.htm and at 
http://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 
http://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 http://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.

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