Full Text PA-96-059
 
HIV:  VIRAL LOAD IN BRAIN AND NEUROBEHAVIORAL CORRELATES
 
NIH Guide, Volume 25, Number 20, June 21, 1996
 
PA NUMBER:  PA-96-059
 
P.T. 34

Keywords: 
  Infectious Diseases/Agents 
  Neuroscience 

 
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
 
PURPOSE
 
It is generally agreed that the presence of HIV within the central
nervous system (CNS) contributes to the development of
neurobehavioral impairments and neurologic syndromes that occur in a
subset of HIV-infected individuals.  However, a direct link between
the presence of virus and HIV-induced motor/cognitive impairments has
yet to be elucidated.  This program announcement solicits research
applications to (1) identify effective ways to quantitate viral load
within the CNS during life; (2) correlate the quantity of virus
within the CNS to the onset and course of neurobehavioral and
neurological changes; (3) identify specific biochemical or
neurochemical alterations in neuronal function as a consequence of
the presence of virus either directly or indirectly; and (4) identify
and test drugs that prevent or reverse the neuronal dysfunction.
Collaborations between neuroscientists and immunologists/virologists
are encouraged but not required.  Fellowships are also solicited
through this program announcement to encourage a broader range of
scientists to conduct research in this field.
 
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 PA,
Viral Load in Brain and Neurobehavioral Correlates, is related to the
priority areas of mental health and mental disorders.  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
 
Eligibility and requirements for different funding mechanisms vary.
Applicants are advised to contact NIMH or NINDS program staff listed
under INQUIRIES for additional information and specific application
procedures.
 
Applications may be submitted by foreign and domestic, 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.
Foreign institutions are not eligible for small grants (R03), First
Independent Research Support and Transition (FIRST) (R29) awards,
program projects (P01), research career awards (K-series), or
fellowships (F-series).  Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as Principal
Investigators.
 
MECHANISM OF SUPPORT
 
The mechanisms available for support by the NIMH are:  research
project grants (R01), FIRST awards (R29), program project grants
(P01), research career programs (K01, K02, K05), fellowship programs
(F30, F31, F32) and small research grants (R03).  The mechanisms
available for support by the NINDS are:  the research projects grants
(R01), FIRST Awards (R29), program project grants (P01), and
fellowships (F32).
 
Because certain grants have special eligibility requirements,
application formats, and review criteria (i.e., small grants and
FIRST awards), applicants are strongly encouraged to consult with
program staff listed under INQUIRIES and obtain the appropriate
additional announcements for those grant mechanisms.
 
RESEARCH OBJECTIVES
 
Central nervous system (CNS) complications occur in a large number of
HIV-infected adults and children.  This is manifested by both motor
and cognitive impairments.  Early manifestation of CNS dysfunction
include slowed processing, forgetfulness, delayed reaction time, or
generalized weakness.  In the most severe instances, patients may
become demented or exhibit partial to complete motor paralysis.
HIV-induced motor/cognitive dysfunction compromises the life of the
affected individual.  The mechanisms underlying CNS dysfunction are
not clear.  It is known that HIV enters the CNS early after
infection, however neurons appear not to be infected.  Instead, virus
is found primarily in cells of the monocyte/macrophage lineage.
Viral infection of other CNS cells has also been demonstrated,
including astrocytes and endothelial cells that make up the blood
brain barrier. Indirect effects of the virus are numerous, including,
but not limited to, changes in the blood brain barrier, increased
cellular trafficking, altered cytokine expression, loss of neurons,
and changes in brain size/quality/density reflected in brain images
seen by various neuroimaging studies.
 
The direct link between the presence of virus in the brain and the
resulting neurobehavioral impairments is not clear. Although virus
within the CNS is assumed necessary for CNS disease, measures to
quantitate virus within the CNS during life are inadequate.
Quantitating viral load in brain tissue at the time of death gives
valuable information. However, this state of the brain at end stage
disease may not adequately address the relationship between viral
load in the brain and the observed neurobehavioral changes prior to
death.  Mechanisms of virus-induced alterations in neuronal function,
either directly or indirectly, must be determined in order to target
appropriate therapies to prevent or correct the neuronal dysfunction.
 
Examples of research that would be an appropriate response to this
Program Announcement include, but are not limited to:
 
o  research to determine methods to effectively quantitate viral load
within the CNS during life;
 
o  research to correlate the quantity of virus within the CNS to
neurobehavioral changes;
 
o  research to identify specific alterations in the structure or
function of neurons as a consequence of the presence of virus either
directly or indirectly;
 
o  research that links HIV-induced altered neuronal structure or
function to impaired motor/cognitive function;
 
o  research that links HIV-induced altered CNS physiology to
motor/cognitive dysfunction;
 
o  research to identify and test drugs that prevent or reverse the
altered CNS physiology or the associated motor/cognitive dysfunction;
 
o  research using any appropriate animal model that will allow the
identification of the mechanisms underlying HIV- induced CNS
dysfunction.
 
Understanding the effects of HIV infection on the CNS will allow the
identification of therapeutic intervention to either reverse or
prevent this devastating complication of HIV.
 
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 is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
 
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 reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.  Investigators also may obtain copies of the policy
from the program staff listed under INQUIRIES.  Program staff may
also provide additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications (with the exception of F30, F31, F32) are to be
submitted on the grant application form PHS 398 (rev. 5/95) and will
be accepted at standard deadlines for AIDS applications as indicated
on page 21 of the application kit.  Applications for fellowships (F-
Series) are to be submitted on form PHS 416-1 (rev. 8/95); the
standard receipt dates for these applications are April 5, August 5,
and December 5.  Both application kits are available at most
institutional offices of sponsored research and may be obtained from
Office of Extramural Outreach and Information Resources, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone
301/710-0267; fax 301/480-0525; email: ASKNIH@ODROCKM1.OD.NIH.GOV.
The title, "HIV: Viral Load in Brain and Neurobehavioral Correlates,"
and number of the program announcement must be typed on the face page
of the application.
 
Applications for the FIRST award (R29) must include at least three
sealed reference letters attached to the face page of the original
application.  FIRST award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.  Applications for individual
NRSAs (F30, 31, 32) must submit at least three completed reference
forms.  These forms are enclosed in the PHS 416-1 (rev. 8/95) kit
used for individual NRSA applications.
 
The completed original application and five legible copies of the PHS
398 or the original and two copies of the PHS 416-1 must be sent or
delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight mail service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with the standard NIH peer review
procedures.  As part of the initial merit review, applications may
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, when applicable.
 
Review Criteria for R01 and R29
 
o  scientific, technical, or medical significance and originality of
proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications.  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 regarding this PA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues relating to the
neurobehavioral impairments associated with HIV infection to:
 
Dianne M. Rausch, Ph.D.
Office on AIDS
National Institute of Mental Health
Parklawn Building, Room 10-75
Bethesda, MD  20857
Telephone:  (301) 443-6100
FAX:  (301) 443-7274
Email:  dr89b@nih.gov
 
Direct inquiries regarding programmatic issues relating to the
neurological complications of HIV infection to:
 
A. P. Kerza-Kwiatecki, Ph.D.
Division of Demyelinating, Atrophic, and Dementing Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 804
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
Email:  ak45w@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Bethesda, MD  20857
Telephone:  (301) 443-3065
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov
 
Dianna Jessee
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  dj35j@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.242, 93.281, and 93.282 for NIMH, and Nos. 93.853
and 93.854 for NINDS.  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 66,
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 PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the nonuse 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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