This Program Announcement expires on June 1, 2004, unless reissued.

HIV-1 INFECTION OF THE CENTRAL NERVOUS SYSTEM

Release Date:  March 20, 2001

PA NUMBER:  PA-01-072 (see replacement PA-04-154)

National Institute of Mental Health
 (http://www.nimh.nih.gov/)
National Institute of Neurological Disorders and Stroke
 (http://www.ninds.nih.gov/)
National Institute on Drug Abuse
 (http://www.nida.nih.gov/)

THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS PA INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA.

THIS PA REPLACES PA-97-017.

PURPOSE

The National Institute of Mental Health (NIMH), the National Institute of 
Neurological Disorders and Stroke (NINDS), and the National Institute on Drug 
Abuse (NIDA) invite research grant applications through this program 
announcement (PA) to support research focused on determining the pathogenic 
mechanisms involved in Human Immunodeficiency Virus (HIV)-1 associated 
neurobehavioral and neurological dysfunction.  The objective of this cooperative 
effort is to foster investigations that will provide the foundation for the 
rapid development of therapeutic interventions to prevent and treat the effects 
of HIV-1 on the central nervous system (CNS).  Applications ranging from basic 
research to clinical diagnosis and treatment are of interest.  Multidisciplinary 
research teams and collaborative alliances are encouraged but not required.  

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 Program Announcement (PA),HIV-1 
Infection of the Central Nervous System, is related to the priority area of 
research on HIV infections.  Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of the 
Federal government.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project grant 
(R01) and exploratory/developmental grant (R21) award mechanisms.  Applicants 
are encouraged to contact program staff listed under INQUIRIES for additional 
information.  Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  The total project period 
for an R01 application submitted in response to this PA may not exceed five 
years.  The total project period for R21 application may not exceed three years.

For all R21 applications and those competing R01 applications requesting up to 
$250,000 direct costs per year, specific application instructions have been 
modified to reflect “MODULAR GRANT” and “JUST-IN-TIME” streamlining efforts 
being undertaken at NIH.  More detailed information about modular grant 
applications, including a sample budget narrative justification pages and a 
sample biographical sketch, is available via the Internet at: 
http://grants.nih.gov/grants/funding/modular/modular.htm.  Applications that 
request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) 
application instructions.

Exploratory/development (R21) grants are limited to an average of $125,000 in 
direct costs per year for up to 3 years.  While variations from year to year are 
permissible, in no case may any year be more than $200,000 in direct costs, and 
total direct costs for the entire project period may not exceed $375,000.  If 
less than 3 years are requested, the maximum amount of the total direct costs 
may not exceed $125,000 per year.  Exploratory/ developmental grants are not 
renewable.  Information and application instructions for the R21 mechanism, 
generally applicable to NIMH, NIDA, and NINDS are available in the NIH Guide for 
Grants and contracts at:  
http://grants.nih.gov/grants/guide/pa-files/PA-99-134.html.  
Applicants for R21 grants are encouraged to consult with NIMH, NIDA, 
or NINDS program staff (see INQUIRIES).

RESEARCH OBJECTIVES

Background

Research on the neuropathogenesis of HIV-1 infection in the last fifteen years 
has significantly improved our understanding of mechanisms of neurologic and 
neuropsychiatric complications associated with Acquired Immune Deficiency 
Syndrome (AIDS).  Improved therapies have also significantly reduced the 
incidence of HIV Associated Dementia (HAD).  However, there are many fundamental 
gaps in our knowledge about mechanisms of HIV-1 entry into the brain, 
establishment of viral reservoirs and reseeding of systemic compartments.  These 
issues are particularly relevant since potent anti-retroviral therapy does not 
penetrate the blood-brain barrier and may not be effective in eradication of CNS 
reservoirs.  Drug resistant viral reservoirs in the CNS may not only be 
important in reseeding of systemic compartments but also contribute to worsening 
of neurologic disease in long-term AIDS survivors.  It is therefore imperative 
to develop an improved understanding of pathophysiology of HIV infection of the 
brain using novel approaches and technologies.  Furthermore research on the 
development of novel drugs that penetrate the blood-brain barrier are needed to 
better manage neurologic and neuropsychiatric complications as well as eradicate 
CNS viral reservoirs.

In an effort to intensify the depth, focus and coordination of key neuro-AIDS 
issues, the NIMH, NINDS and NIDA are jointly issuing this Program Announcement.  
Applicants are encouraged to contact Program Staff of the appropriate institute 
regarding specific areas of interest.       

Studies of HIV-1 infection of the brain have been slowed by the lack of well 
characterized infected human CNS tissues. Such tissue samples [brain, cerebral 
spinal fluid (CSF), blood] from HIV patients are currently available from the 
National NeuroAIDS Tissue Consortium (http://www.hivbrainbanks.org), which can 
be used as a resource for research studies.  

The following are examples of research areas that are pertinent to this Program 
Announcement. 

I. Research on the mechanisms of establishment of CNS viral reservoirs. Some of 
the areas of study and questions may include:	

a. Analysis of timing of establishment of CNS reservoirs (Can the establishment 
of these reservoirs with early drug intervention such as potent anti-retroviral 
therapy be prevented?  Is the establishment of CNS reservoirs different from 
reservoirs in systemic compartments?)

b. An in-depth study of the cell populations that serve as reservoirs in CNS

c. Whether there are low levels of viral replication in the CNS reservoirs and 
whether that contributes to the emergence and evolution of drug resistant 
strains

d. Whether viral strains evolve and establish heterogeneity in different regions 
and cell populations in the brain, and whether they are different from blood-
derived viruses

II. Research on mechanisms of reseeding of the peripheral compartment from the 
CNS - some of the questions and approaches may include:

a. Whether HIV-1 reenters the peripheral circulation, and if so, is it in 
association with reverse migrating cells or as free virus

b. Sequencing studies using neurovirulent strains to determine whether brain-
specific sequences can be detected in peripheral compartments after cessation of 
potent anti-retroviral therapy; tracking molecular signatures of virus reseeding 
from the CNS to the periphery

III. Research on the role of CNS viral load in contributing to neurologic and 
neuropsychiatric dysfunction (Is the amelioration of CNS dysfunction following 
potent anti-retroviral therapy associated with changes in CNS viral load?  Is 
the reduction in peripheral viral load a good predictor of improvement of CNS 
symptoms and can this serve as a sufficient marker to monitor brain specific 
symptoms?)

IV. Assessment of HIV-induced CNS degeneration and dysfunction using novel 
imaging techniques [positron emission tomography (PET), magnetic resonance 
spectroscopy (MRS), magnetic resonance imaging (MRI), functional magnetic 
resonance imaging (fMRI), functional magnetic resonance spectroscopy (fMRS): 

a. Studies of association of unique imaging signatures with specific HIV-induced 
neuropsychiatric or cognitive dysfunction

b. Analysis of blood-brain barrier (BBB) abnormalities following HIV-1 infection 

c. Studies of subtle HIV-1 induced changes in brain metabolism by imaging 
techniques

d. Use of various imaging technologies to track improvements in HIV induced CNS 
dysfunction following potent anti-retroviral therapy

V. Research to develop HIV-1 therapeutic agents capable of penetrating the BBB 
(alternate approaches may include manipulation of efflux transporters, such as 
P-glycoproteins, to improve access of anti-HIV agents across the BBB) 

VI. Research on the co-modulation of neural processes and related biologicals 
systems by HIV-1 and other neurotoxins (e.g., methamphetamine, opiates or 
cocaine) and/or therapeutic agents (e.g., azidothymidine (AZT), methadone) 

VII. Research to determine the role of opportunistic infections in 
neurobehavioral and neurological complications of HIV infection
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 

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 biomedical and behavioral 
research projects involving human subjects, unless a clear and compelling 
rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

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.  
Reviewers are cautioned that their anonymity may be compromised when they 
directly access an Internet site.

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact the program contacts listed under 
INQUIRIES with any questions regarding their proposed project and the goals of 
this PA.

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines for AIDS 
applications as indicated in the application kit (January 1, May 1 and September 
1).  Application kits are available at most institutional offices of sponsored 
research and from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910, telephone (301) 435-0714, Email: GrantsInfo@nih.gov.  Applications 
are also available on the World Wide Web at: 
http://grants.nih.gov/grants/forms.htm.

SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS

The modular grant concept establishes specific modules in which direct costs may 
be requested as well as a maximum level for requested budgets.  Only limited 
budgetary information is required under this approach.  The just-in-time concept 
allows applicants to submit certain information only when there is a possibility 
for an award.  It is anticipated that these changes will reduce the 
administrative burden for the applicants, reviewers and Institute staff.  
Additional information about modular grant applications is available at: 
http://grants.nih.gov/grants/funding/modular/modular.htm.    

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to a 
total direct cost request of $250,000 per year.  (Applications that request more 
than $250,000 direct costs in any year must follow the traditional PHS 398 
application instructions.)  The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total 
Direct plus Facilities and Administrative (F&A) costs] for the initial budget 
period.  Items 8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398.  It is not required and 
will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page.  (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.)  At the top of the page, enter the total direct costs requested for each 
year.  This is not a Form page.

o  Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should be 
provided.  However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000.  List the individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of all personnel, and the role 
on the project.  Indicate whether the collaborating institution is foreign or 
domestic.  The total cost for a consortium/contractual arrangement is included 
in the overall requested modular direct cost amount.  Include the Letter of 
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall qualifications 
of the research team.  A biographical sketch is required for all personnel, 
following the instructions below.  No more than three pages may be used for each 
person.  A sample biographical sketch may be viewed at: 
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on research 
projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST - This page should be completed and submitted with the application.  
If the F&A rate agreement has been established, indicate the type of agreement 
and the date.  All appropriate exclusions must be applied in the calculation of 
the F&A costs for the initial budget period and all future budget years.

o  The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information is 
necessary following the initial review.

Applicants planning to submit an investigator-initiated new (Type 1), competing 
continuation (Type 2), competing supplement, or any amended/revised version of 
the preceding grant application types requesting $500,000 or more in direct 
costs for any year are advised that he or she must contact the Institute program 
staff before submitting the application, i.e., as plans for the study are being 
developed.  Furthermore, the application must obtain agreement from the 
Institute staff that the Institute will accept the application for consideration 
for award.  Finally, the applicant must identify, in a cover letter sent with 
the application, the staff member and Institute who agreed to accept assignment 
of the application.

This policy requires an applicant to obtain agreement for acceptance of both any 
such application and any such subsequent amendment.  Refer to the NIH Guide for 
Grants and Contracts, March 20, 1998 at:  
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

Any application subject to this policy that does not contain the required
information in a cover letter sent with the application will be returned to the 
applicant without review.

The title and number of the program announcement must be typed on line 2 of the 
face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and 5 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical merit 
by an appropriate scientific review group convened in accordance with the 
standard NIH peer review procedures.  As part of the initial merit review, all 
applications will receive a written critique and undergo a process in which only 
those applications deemed to have the highest scientific merit, generally the 
top half of applications under review, will be discussed, assigned a priority 
score, and receive a second level review by the appropriate national advisory 
council or board.

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 the 
application in order to judge the likelihood that the proposed research will 
have a substantial impact on the pursuit of these goals.  Each of these criteria 
will be addressed and considered in assigning the overall score, weighting them 
as appropriate for each application.  Note that the 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, an investigator 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 this study address an important problem?  If the aims of 
the application are achieved, how will scientific knowledge be advanced?  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?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the research.  
Plans for the recruitment and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research

o  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.

AWARD CRITERIA

Applications will compete for available funds with all other recommended 
applications assigned to the Institute.  The following will be considered in 
making funding decisions:  Quality of the proposed project as determined by peer 
review, availability of funds, and program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Jeymohan Joseph, Ph.D.
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6202, MSC 9619
Bethesda, MD 20892-9619
Telephone:  (301) 443-3012
FAX: (301) 443-9719
E-Mail: jjeymoha@mail.nih.gov

A.P. Kerza-Kwiatecki, Ph.D.
Neural Environment
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2115, MSC 9521
Bethesda, MD 20892-9521
Telephone:(301)496-1431
FAX: (301) 402-2060
E-Mail: ak45w@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
Telephone:(301)443-1887
Fax: (301) 594-6043
E-Mail: cs107m@nih.gov

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX:  (301) 443-6885
E-Mail:  Diana_Trunnell@nih.gov

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard , Room 3290, MSC 9537
Bethesda, MD 20892-9537
Telephone: (301) 496-7416
FAX: (301) 402-0219
E-Mail: 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
Telephone:(301) 443-6710
FAX: (301) 594-6849
E-Mail: gf6s@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.242 (NIMH), No. 93.853 (NINDS), and No. 93.279 (NIDA).  Awards are made under 
authorization of the Public Health Service Act as amended (42 Usc 241 and 284) 
and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-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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