NON-HUMAN PRIMATE MODELS FOR HIV/CNS DISEASE

Release Date: January 29, 1999

RFA:  MH-99-009

P.T.

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

Letter of Intent Receipt Date:  April 13, 1999
Application Receipt Date:  May 13, 1999

PURPOSE

The National Institute of Mental Health (NIMH) and the National Institute of
Neurological Disorders and Stroke (NINDS) solicit research using non-human
primates infected with simian immunodeficiency virus (SIV) as a model for HIV
infection of humans to study the effects of lentiviral infection of the CNS
and the resulting neuropsychologic and neurologic pathology.  The mechanisms
by which HIV causes neurobehavioral impairments, either direct or indirect,
must be determined if therapeutic interventions can be realized.  The use of
the SIV model of AIDS provides a critical opportunity to study the mechanisms
underlying HIV neuropathogenesis.

This request for applications (RFA) will solicit research grants directed
toward expanding the use of SIV-infected non-human primates to address the
effects of this virus on the CNS to increase understanding of the resulting
pathology and identify therapeutic targets for prevention and/or treatment of
the functional and neurological consequences.

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, Non-Human Primate Models for
HIV/CNS Disease, is related to the priority area of neurological effects of
HIV infection.  Potential applicants may obtain a copy of "Healthy People
2000" at http://www.crisny.org/health/us/health7.html

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 RFA will use the National Institutes of Health (NIH) research project
grant (R01) award mechanism.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.  The
total project period for an application submitted in response to this RFA may
not exceed 5 years.  This RFA is one-time solicitation.  Future unsolicited
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review
procedures.  The anticipated award date is September, 1999.

FUNDS AVAILABLE

There will be approximately $2.5 million in FY 1999 to fund new and/or
competitive continuation grants in response to this RFA.  Although the
financial plans of the sponsoring Institutes 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 applications of outstanding scientific
and technical merit.

RESEARCH OBJECTIVES

Background

The neuropathogenesis of human immunodeficiency virus (HIV)-associated
dementia has remained elusive, despite identification of HIV as the causal
agent.  A number of contributing factors have been identified, however the
series of events that culminate in motor and cognitive impairments following
HIV infection of the central nervous system (CNS) are still not known.  HIV
does not readily infect neurons, rather the primary infected cells of  the CNS
are brain macrophages and microglia.  The pathophysiology of these cells that
occurs with HIV disease is likely to be similar, at least in part, to that
which occurs in several neurodegenerative diseases, such as multiple
sclerosis, Alzheimer's and Parkinson's diseases, and perhaps many other. 
Thus, studies of neurodegenerative pathways are important and valuable to the
elucidation of the etiology of many nervous system disorders.

The importance of the SIV model of AIDS to aid in deciphering and
understanding the mechanisms underlying human AIDS neuropathogenesis is
supported by several critical facts. HIV and SIV are genetically and
structurally similar, and both viruses utilize the CD4 receptor to gain entry
into the cell.  The clinical manifestations of the disease caused by HIV in
humans is comparable in many ways to the disease caused by SIV in non-human
primates.  The incidence of neuropsychologic and neurologic disease that
occurs in HIV-infected humans also occurs in SIV-infected monkeys, and the
neuropathologic findings in both populations are nearly indistinguishable.

Better understanding of HIV-associated neuropathogenesis will provide the
opportunity to interrupt progression and to design better treatments for HIV-
associated dementia.  This becomes increasingly important as patients live
longer yet still harbor HIV-infected cells in the CNS.  The use of the SIV
model will allow the identification of neuropathological markers important for
HIV-associated dementia.

Studies funded in response to this RFA include but are not limited to:

o  studies to test for motor/cognitive impairments in SIV-infected monkeys and
identify neuropathological and biochemical correlates;

o  studies to identify and characterize neurovirulent virus for use in these
studies;

o  studies to correlate neurologic findings with immunologic markers of
disease progression or response to therapies;

o  studies on the genotype and phenotype of SIV isolates that cause CNS
pathology and overt manifestations of CNS disease in infected monkeys;

o  the cellular targets of SIV infection within the CNS;

o  the relationship between nervous system disease in SIV-infected monkeys and
peripheral immunologic parameters of disease development;

o  the genetic elements related to SIV/AIDS that determine surface
glycoprotein expression, regulatory gene expression (i.e., nef, tat), and the
differences between distinct cellular tropic phenotypes and pathologic
potential;

o  identification and characterization of the selection of neurotropic strains
in vivo;

o  expansion of vaccine and pathogenesis studies to include questions related
to SIV-induced nervous system disease;

o  studies to identify altered expression of neuropeptides or
neurotransmitters that may contribute to the associated dysfunction.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  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 Institute
staff to estimate the potential review workload and avoid conflict of interest
in the review.

The letter of intent is to be sent to Dr. Dianne Rausch at the address listed
under INQUIRIES by the letter of intent receipt date listed in the heading of
this RFA.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  These forms 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.

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  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.

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:

Dianne Rausch, Ph.D.
Office of AIDS Research
National Institute of Mental Health
6001 Executive Boulevard., Room 6209 MSC 9619
Rockville, MD  20892-9619

Applications must be received by May 13, 1999.  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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIMH 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 an appropriate peer review group convened by
NIMH in accordance with the review criteria stated below.  As part of the
initial merit review, a process will be used by the initial review group in
which 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 the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the National
Advisory of Mental Health and National Advisory Neurological Disorders and
Stroke Advisory Councils.

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 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,
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

Because of the limited availability of non-human primates, collaborative
efforts and the extension of current virological and immunological studies
using non-human primates to address the neurological complications of SIV/HIV
infection are strongly encouraged.

Schedule

Letter of Intent Receipt Date:    April 13, 1999
Application Receipt Date:         May 13, 1999
Peer Review Date:                 June 1999
Council Review:                   Aug/Sep 1999
Earliest Anticipated Start Date:  Sept 1, 1999

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.

INQUIRIES

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:

Dianne Rausch, Ph.D.
Office of AIDS Research
National Institute of Mental Health
6001 Executive Boulevard, Room 6209, MSC 9619
Rockville, MD  20892-9619
Telephone:  (301) 443-7281
FAX:  (301) 443-9719
Email:  dr89b@nih.gov

A. P. Kerza-Kwiatecki, Ph.D.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2117, MSC 9160
Bethesda, MD  20892-9160
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
6001 Executive Boulevard, Room 6115, MSC 9605
Rockville, MD  20852-9605
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3261, MSC 9190
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email: dj35j@nih.gov

The National Institute of Drug Abuse is interested in applications on studies
involving substances of abuse focusing on the above or related research areas. 
Questions concerning studies of interest to the National Institute of Drug
Abuse should be addressed to:

Charles Sharp, Ph.D.
National Institute of Drug Abuse
6001 Executive Boulevard, Room 4284 MSC 9555
Bethesda, MD  20892-9555
Telephone:  (301) 443-1887
FAX:  (301) 594-6043
Email:  cs107m@nih.gov

Nonhuman primate research opportunities may be available through the National
Center for Research Resources-supported Regional Primate Research Centers
Program (see NIH Guide Notice, January 17, 1997, "Procedures for Accessing
Regional Primate research Centers).  Questions may be directed to:

Jerry Robinson, Ph.D.
National Center for Research Resources
6705 Rockledge Drive, Room 6172
Bethesda, MD  20892
Telephone:  (301) 435-0744
FAX:  (301) 480-3819
Email:  jerryr@ncrr.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No.93.242 (NIMH) and 93.854 (NINDS).  Awards are made under authorization of
the Public Health Service 5600 Fishers Lane 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 policy as stated in the NIH Grants Policy Statement
(October 1, 1998).

The PHS 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 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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