CENTRAL NERVOUS SYSTEM AS THE HIV SANCTUARY

Release Date:  September 4, 1998

RFA:  NS-99-002

P.T.

National Institute of Neurological Disorders and Stroke
National Institute of Drug Abuse
National Institute of Mental Health

Letter of Intent Receipt Date: November 1, 1998
Application Receipt Date:  December 11, 1998

PURPOSE

The National Institute of Neurological Disorders and Stroke (NINDS), the
National Institute of Drug Abuse (NIDA), and the National Institute of Mental
Health (NIMH) invite investigator-initiated research grant applications that
address the potential role of the central nervous system (CNS) as a reservoir
for HIV.  HIV can penetrate the CNS, and a subset of HIV-infected individuals
develop motor and/or cognitive impairments to varying degrees.  The mechanisms
responsible for this CNS dysfunction are not well known.  Direct injury by the
virus or viral components and the abnormal secretion of cytokines likely
damage nervous system cells.  It is assumed that halting HIV replication
and/or elimination of virus would prevent CNS damage.  This Request for
Applications (RFA) solicits research applications to study mechanisms of HIV
trafficking through the blood brain barrier (BBB), CNS viral localization,
control and eradication, and the CNS as a potential virus reservoir. 
Applications addressing the anti-HIV CNS drug discovery, drug delivery and
pharmacology are especially encouraged.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Central Nervous System As The
HIV Sanctuary, is related to the priority area of neurological complications
of HIV infection.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and non-
profit organizations; public and private institutions, 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

The mechanism of support will be the individual research project grant R01. 
The total requested project period for an application submitted in response to
this RFA may not exceed five years.  Because the nature and scope of the
research proposed in response to this RFA may vary, it is anticipated that the
size of an award will vary also.  Collaborative efforts between research
centers and sites are acceptable.  Budget escalation's in future years should
be limited to 3% of recurring costs.  Some sponsoring Institutes may
administratively limit the duration and the budget level of an award.  The
anticipated award date is June 1, 1999.

Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.

This RFA is one-time solicitation.  Future competing continuation applications
will compete with all investigator initiated applications and will be reviewed
according to the customary peer review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the first
year of support for all awards made under this RFA in FY 1999 will be $1.8M. 
The usual PHS policies governing grants administration and management will
apply.  Although this program is provided for in the financial plans of the
participating institutes, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose and the receipt of a sufficient number
of applications of high scientific merit.  Funding beyond the first and
subsequent years of the grant will be contingent upon satisfactory progress
during the preceding years and availability of funds.

RESEARCH OBJECTIVES

Background

HIV can penetrate the nervous system resulting in a wide range and severity of
pathological and clinical manifestations.  Gaps in neuro-AIDS knowledge and in
research efforts represent an opportunity to NINDS and other Institutes and
Centers (IC) of the NIH family to contribute to progress in newly identified
areas.  The "NIH Plan to Implement Recommendations of the NIH AIDS Research
Program Evaluation Task Force" has been developed in response to the 1996
"Report of the NIH AIDS Research Program Evaluation Task Force", and to
provide new research initiatives for NIH HIV/AIDS research programs. 
Concurrently, and as the result of these recommendations, a number of
workshops and panels have been convened to re-examine  research programs and
priorities of ICs.  The outgrowth of these activities have led to stronger
cooperative ventures among the Institutes with interest in neuro-AIDS,
particularly in such high priority areas as the role of the BBB in CNS HIV
infection, neuropathogenesis, and anti-HIV strategies.

This RFA has been developed in order for the NINDS to implement
recommendations relevant to HIV infection of the nervous system, especially
the question whether the CNS functions as the HIV sanctuary, and to provide
other NIH Institutes a joint vehicle  in our shared anti-AIDS mission.

Research Objectives and Scope

HIV infection frequently result in dementia and other neurological disorders. 
During the last decade, numerous studies have indicated that while microglial
cells are the primary target for HIV infection, other cells including
astrocytes and capillary endothelial cells of the BBB may also be infected
with low viral levels.  Therefore, much attention has been paid to the role of
microglial cells with great emphasis on altered levels of cytokines,
biochemical pathways, and more recently, chemokines in the neuropathogenesis
of AIDS.  The presence of HIV in microglial and capillary endothelial cells
suggests that one mode of entry of HIV into the CNS may be mediated by
trafficking of the infected macrophages across the BBB.

Brain pathology in HIV-infected individuals does not correlate with the viral
load in the brain.  This suggests that an indirect mechanism independent from
viral presence or replication may contribute to CNS pathology.  Several recent
observations suggest that interaction between virus, endothelial cells, and
astrocytes can cause cell damage via regulatory proteins in the absence of
viral replication by deregulating the cascade of events that control normal
cell function.  Thus, future attempts to understand  the molecular
pathogenesis of HIV-induced CNS dysfunction may include the study of
communication between endothelial cells and astrocytes in the presence of
viral regulatory proteins, drugs of abuse, and factors released by infected
microglial cells.  These studies may focus  on deregulatory events involving
indirect pathways, with the anticipation of developing more effective anti-
viral strategies.  Recent reports indicate that highly active anti-retroviral
(HAART) therapy is effective in reducing HIV mRNA in the cerebrospinal fluid
(CSF) to levels that appear to be similar to the reduction observed in the
general circulation.  This is surprising because macrophages and microglial
cells, which are believed to be the main reservoirs of replicating HIV in the
brain, can be persistently infected and produce virus without cytolysis, and
consequently are expected to exhibit slower turnover during therapy compared
to lymphocytes.  It has also been shown that in vitro opioids can modulate the
growth of HIV in these cells.

The objective of this RFA is to determine if the CNS serves as  a source of
reinfection, especially following  the systemic anti-HIV treatment. Supporting
studies could be proposed for elucidation of mechanisms of HIV trafficking
through blood brain barrier, development of anti-HIV CNS drugs, drug delivery
and pharmacology, and control of the CNS viral dissemination and/or HIV
eradication or neutralization.

Examples of relevant research include, but are not limited to, the following:

o  Development of methodology to modulate BBB to control viral dissemination
and viral load, and to enhance drug delivery;

o  Analysis of the mechanisms underlying the neurological and neurobehavioral 
consequences of HIV infection of the CNS and peripheral nervous system (PNS);

o  Quantitation of HIV burden in astrocytes, neurons, and cells of the immune
system of patients with different levels of neurological involvement, and
following anti-viral therapy;

o  Identification of viral genes or gene products that affect neurovirulence
and/or neuroinvasiveness of HIV;

o  Assessment of the effect of viral load, viral strain, viral products, and
HIV location on neuropathogenicity;

o  Elucidation of the role of the immune system, intracellular signaling
pathways, receptors, and cytokines in viral tropism, and pathogenicity, and
HIV associated dementia;

o  Investigation of signal transduction which may induce recruitment and
proliferation of inflammatory cells and further cytokine/chemokine
dysfunction;

o  Refinement and assessment of structural imaging of the brain using
computerized tomography (CT), magnetic resonance (MR), MR spectroscopy and
functional MR, single photon emission computerized tomography (SPECT), and
positron emission tomography (PET) in diagnosis and treatment of neurological
disease;

o  Identification of surrogate markers for use in rapid and early diagnostic
tests of HIV infection, and for the measure of neuropathogeneic damage and
treatment success;

o  Studies of the CNS viral load versus peripheral blood as a marker/measure
of neurological impairment;

o  Development of new therapeutics and clinical trials for the nervous system 
diseases/disorders, and measurement of new drugs' effectiveness in treatment
of CNS and PNS HIV disease;

o  Development of animals, in vitro systems, and computer models of HIV
disease, and potential treatments;

o  Elucidation of the influence of drugs of abuse and associated
conditions/illnesses, e.g., head trauma, nutritional problems, hepatitis,
tuberculosis, comorbid mental illness, on the blood brain barrier and the
cytopathologic processes involved in HIV infection, persistence and
replication within the nervous system, including appropriate animal models.

o  Determination of the effects of prenatal exposure to drugs of abuse in HIV
infected children (and appropriate animal models) on the developmental
trajectory of the CNS as an HIV reservoir;

o  Investigation of possible common links for neurodegenerative diseases such
as Alzheimer's disease, Parkinson's disease, and HIV-dementia, where
microglial activation is a common pathway for neural destruction;

o  Determination of the relationship of HIV to opportunistic disease,
development and evaluation of new strategies for prevention, assessment, and
treatment of opportunistic and parasitic infections, and HIV-associated
malignancies.

The areas outlined above are not intended to be all-inclusive.

SPECIAL REQUIREMENTS

In addition to yearly progress reports, the Principal Investigators of grants
funded under this RFA will provide brief summary reports of the outcomes of
the research at the conclusion of the funding period and one year later.  The
reports will summarize the major scientific knowledge gained and identify
other substantive outcomes such as publications, patents, and new grants,
contracts, or research studies based on this research.

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 subpopulations 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 that inclusion is
inappropriate with respect to the health of the subjects of 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
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research", which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994.

Investigators may obtain copies from these sources or from program staff
listed in INQUIRIES below who may also provide additional relevant information
concerning the policy.

NIH POLICY AND GUIDELINES ON THE 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

LETTER OF INTENT

Prospective applicants are asked to submit, by November 1, 1998, a letter of
intent that includes a descriptive title of the overall proposed research, the
name, address and telephone number of the Principal Investigator, and the
number and title of this RFA.  Although the letter of intent is not required,
is not binding, does not commit the sender to submit an application, and does
not enter into the review of subsequent applications, the information that it
contains allows review to estimate the potential review workload and to avoid
conflict of interest in the review.  The letter of intent is to be sent to Dr.
Kerza-Kwiatecki at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact program staff listed under
INQUIRES with any questions regarding the responsiveness of their proposed
project to the goals of this RFA.

Applications are to be submitted on the research grant application form PHS
398 (rev. 5/95).  Application kits are available at most institutional offices
of sponsored research and may be obtained 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.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number "NS-99-002" and the title
of this RFA "CENTRAL NERVOUS SYSTEM AS THE HIV SANCTUARY" must be entered.

The RFA label available in the application form PHS 398 must be affixed to the
bottom of the face page.  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.

If the application submitted in response to this RFA is substantially similar
to a grant application already submitted to the NIH for review, but that has
not yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical applications
be reviewed by different review committees.  Therefore, an application that is
essentially identical to one that has already been reviewed cannot be
submitted in response to this RFA.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

Submit a signed, typewritten original of the application, including the
checklist, and five signed, exact, single-sided photocopies, and all five sets
of appendix material 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)

Applicants from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research.  If so,
a letter of agreement from either the GCRC Program Director or Principal
Investigator should be included with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the NIH Center
for Scientific Review (CSR) and for responsiveness by sponsoring Institutes
staff.  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
a Scientific Review Group (SRG) established by the NINDS, and convened in
accordance with NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique, and may undergo a
process in which only those applications deemed to have the highest scientific
merit will be discussed, assigned a priority score, and receive a second level
review by the national advisory council or board, when applicable.

Review Criteria

The five criteria to be used in the evaluation of grant applications are
listed below.  To put those criteria in context, the following information is
contained in instructions to the peer reviewers.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques 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 by the reviewers 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 a 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 method? 
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?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific goals of the
research and plans for the recruitment and retention of subjects; adequacy of
plans for including children as appropriate for the scientific goals of the
research; the provisions for the protection of human and animal subjects; and
the safety of the research environment.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merit
as determined by peer review, program balance, and the availability of funds. 
The earliest anticipated date of award is June 1, 1999.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding programmatic issues to:

A. P. Kerza-Kwiatecki, Ph.D.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 504
Bethesda, MD  20892
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
Email:  ak45w@nih.gov

Sander G. Genser, M.D., M.P.H.
Center for AIDS and Other Medical Consequences of Drug Abuse
National Institute on Drug Abuse
Parklawn Building, Room 10A-08
Rockville, MD  20857
Telephone:  (301) 443-1801
FAX:  (301) 594-6566
Email:  sg73f@nih.gov

Charles W. Sharp, Ph.D
Division of Basic Research
National Institute on Drug Abuse
Parklawn Building, Room 10A-31
Rockville, MD  20857
Telephone:  (301) 443-1887
FAX:  (301) 594-6043
Email:  cs107m@nih.gov

Diane M. Rausch, Ph.D.
Office of AIDS Research
National Institute of Mental Health
Parklawn Building, Room 18-101
Rockville, MD  20857
Telephone:  (301) 443-6100
FAX:  (301) 443-9719
Email:  dr89b@nih.gov

Direct inquiries regarding fiscal matters to:

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
7550 Wisconsin Avenue, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  dj35j@nih.gov

Jack R. Manischewitz, Ph.D.
Grants Management Branch
National Institute on Drug Abuse
Parklawn Building, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  jm198m@nih.gov

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov

Schedule

Letter of Intent Receipt Date:  November 1, 1998
Application Receipt Date:       December 11, 1998
Earliest Award Date:            June 1, 1999

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.855, 93.279, 93.242, and 93.853.  Awards are made under authorization of
the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.  Awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy Statement
(April 1, 1994).

The Public Health Service strongly encourages all grant 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 for 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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