Subject: (Copy) NIH GUIDE - Vol. 20, No. 5, February 1, 1991 - RFA AI-9
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 31 Jan 91 08:18 EST

Good Morning Paul,
   The way it looks there will be several of these coming to you
this morning.  Please post this as:
        RFAAI-91-04.910201
 Thanks.  Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR APPLICATIONS
 
DEVELOPMENT OF MODELS FOR PEDIATRIC AIDS
 
RFA AVAILABLE:  AI-91-04
 
P.T. 34; K.W. 0715008, 0755020, 0770005
 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:  March 11, 1991
Application Receipt Date:  April 22, 1991
 
The National Institute of Allergy and Infectious Diseases
(NIAID) invites applications for individual research project
(RO1) grants to conduct basic research in the development of
animal models and in vitro models for pediatric
human immunodeficiency virus (HIV)
infection and disease.  HIV is now recognized as the
causative agent of the Acquired Immunodeficiency Syndrome
(AIDS).  However, the disease that occurs in the pediatric
population is different from the disease that occurs in
adults.  Disease in very young children progresses more
rapidly than in adults and the range of opportunistic
infections (OIs) differs with more bacterial infections
occurring in children.  Further, the immunosuppressive
effects of HIV are superimposed on immature
immune and nervous systems in children.  Thus, the pathogenesis of
lentivirus infections and the associated opportunistic
infections are likely to be different from adults in developing animals.
Animal models of fetal or neonatal
infection with lentiviruses related to HIV and in vitro
models of placental infection are needed to study these
aspects of disease and facilitate the identification and
evaluation of therapies with greatest potential for treating
these special populations.
 
Research efforts considered responsive to this RFA include
delineation of the events leading to the establishment of
primary infection in fetal or neonatal animals, the
mechanisms of virus spread, viral or placental factors
modulating infection, and the outcomes of infection during
development, including immune suppression and opportunistic
infections.  Investigators should plan to apply the models
described above to the design of new anti-HIV therapies to
prevent or interrupt the transmission of HIV from mother to
offspring.  The models should also be applicable for testing
the efficacy of such therapies.
 
I.    BACKGROUND
 
NIAID is playing a central role in the investigation of
AIDS.  Research
efforts directed toward the pathogenesis, prevention, and
treatment of the disease and its sequelae have intensified.
The NIAID has undertaken a lead role in organizing
scientists into National Cooperative Drug Discovery Groups
for the Treatment of HIV Infection (NCDDG-HIV) and of the
opportunistic infections associated with AIDS (NCDDG-OI).
In vitro screening of potential therapies and the more
targeted approach of the NCDDG's have proven extremely
valuable and have led to identification of several new
therapies currently undergoing preclinical development as
well as several therapies in clinical trials.  The NIAID
also supports individual investigators in their research
efforts toward the discovery and development of therapies
for AIDS.  The NIAID supports and oversees the AIDS Clinical
Trials Groups (ACTG), the premier NIH-funded U.S. clinical
trials effort for the evaluation of agents directed against
HIV and against the
IOs and malignancies that are sequelae
of HIV infection.
 
To date most preclinical drug development efforts have
concentrated on generating data to support clinical trials
in HIV-infected adults.  Studies focused on the unique
aspects of infection of the fetus and of the neonate need to
be expanded so that information can be gained concerning the
unique targets for therapies that might be present in this
population.  Children born to HIV-positive women are one of
the fastest growing populations of AIDS patients.
Therefore, the NIAID now wishes to expand the scope of
research currently being conducted in this area.
 
The rational design and optimization of therapies for
preventing transmission or treating the neonate and
pediatric populations require a thorough understanding of
the disease process in the fetus and in developing animals.
If more effective therapies are to be found for pediatric
HIV disease, the disease and mechanisms of infection must be
more clearly defined.  Aggressive research is necessary to
develop models in which questions of pathogenesis and
mechanism of infection may be answered.  Elucidation of the
mechanisms of transplacental infection of the fetus (via
free virus or infected cells) and the effects of infection
on the developing immune system and nervous system is
critical.  This research needs to include investigation of
the regulation of virus expression in fetal or placental
tissues and definition of viral and/or cellular factors that
may effect transplacental infection.  Such research in
appropriate models will facilitate the identification and
exploitation of methods to prevent HIV transmission and/or
prevent the spread of infection in the fetus, neonate or
pediatric patients.
 
II.  OBJECTIVES AND SCOPE
 
NIAID wishes to stimulate research to develop animal models
and in vitro models to study the origin, consequences, and
treatment of pediatric infection with HIV, lentiviruses, or
relevant retroviruses closely related to HIV.  The models
should be used to examine the pathogenesis of infection in
the fetus or neonate, to examine effects of infection on
developing rather than adult organisms, to investigate
infection of the placenta and mechanisms of transplacental
infection, and to define viral and placental factors that
affect transplacental infection.
 
Specifically, research efforts considered responsive to this
Request for Applications (RFA) are to develop and use:  (i) an in
vitro model of infection of placenta with HIV suitable for
examining the regulation and pathogenesis of HIV and for
identifying unique targets for new therapies; and/or (ii) an
animal model of transmission of virus, studying transplacental
transport of virus or infected cells, the mechanisms of
infection, and targets for therapies; or (iii) an animal model of
lentivirus infection of fetal or neonatal animals for studying
the pathogenesis of the virus, development of disease, and the
action of therapies designed to prevent transmission; and/or (iv)
an animal model, using a lentivirus or relevant retrovirus, to
define the viral and/or cellular factors that effect
transplacental infection and that represent potential targets for
new therapies.  Investigators should plan to apply the models
described above to the design and preclinical evaluation of
anti-HIV therapies to prevent or interrupt the transmission of
HIV from mother to offspring.  In addition, use of HIV or a
lentivirus such as SIV is preferred.  Use of other retroviruses
may be considered responsive IF there is evidence presented that
it models HIV disease closely.  Applications that involve
collaborating scientists or institutions are encouraged, but not
required, for response to this announcement.
 
Research plans to:  (i) solely evaluate various compounds for
their ability to cross the placenta in an animal model, (ii)
evaluate vaccine-related therapies or immune responses,
(iii) develop or use models that employ murine leukemia
retroviruses, or (iv) develop or use transgenic models or
models in which virus is injected directly into fetuses as a
model of transmission are not considered responsive to this
announcement.
 
Recent reports have documented HIV infection of cells within
the human placenta.  However, little is known about
regulation of HIV expression, viral replication, or
mechanisms of infection in the placenta.  For example,
Hofbauer cells, macrophage-like cells present within the
placenta, may act as a reservoir for infection of both
maternal and fetal cells.  Factors that regulate HIV
expression in the placenta should also be investigated to
determine whether there are unique potential therapeutic
targets in the placenta.  Similarly, there may be viral and/or
cellular factors that modulate HIV expression, infectivity,
or transmission within the placenta.  Studies directed
toward these and other questions related to infection of
human placenta by HIV are greatly needed.
 
Although it is assumed that HIV infection of the fetus
occurs by some type of transplacental transmission of the
virus, virtually nothing is known about the actual
mechanism(s) of virus transport.  Questions remain about
whether virus is transmitted as free virus or by infected
cells and little information is available on virus uptake or
release from cells within the placenta.  Once the routes of
transport of virus are determined, the rational selection or
design of therapies to interrupt transmission will be
greatly facilitated.  For example, if transmission occurs
via infected cells, therapies to reduce free virus are not
likely to be effective.  While certain information may be
obtained from studies using HIV and human placental cells in
vitro, other models using pregnant animals, and other
lentiviruses may contribute valuable information on
transmission in vivo.
 
Prenatal or perinatal infection with several pathogens is known
to occur in humans.  For CMV, HSV, rubella, and toxoplasma,
disease and consequences of infection in the infant are different
from consequences in adults.  This difference in disease course
and severity may reflect the immature immune system of the infant
at the time of infection.  Targets for HIV infection include the
immune system and the nervous system, both of which are still
developing after birth in humans and most primates.  The
pathogenesis of HIV may differ in the fetus or neonate compared
to adults due to the immaturity of the target organs and, in
particular, the immaturity of the immune system.  Indeed, OIs
differ in infants and adults infected with HIV.  There may also
be broader differences in the response of the developing organism
to infection.  For example, failure to thrive or delayed growth
are associated with HIV infection of very young children but have
no real correlate in adult patients.
 
These differences point to a critical need to develop new
animal models using a lentivirus or relevant retrovirus
infection that accurately reflect the characteristics of
disease unique to developing animals.  Animal models are
also needed to evaluate the role of the developing immune
system in the pathogenesis of HIV infection and the impact
of infection on specific developmental patterns, including
the effects of infection on development of the immune and
nervous systems.  Results from this research on the origin
and consequences of lentivirus infection of the placenta and
developing animals should be applied to the identification
and evaluation of methods to prevent HIV transmission,
spread, and its sequelae.
 
III.  MECHANISM OF SUPPORT
 
This RFA will use the R01 grant mechanism.  The NIAID has
allocated $1,000,000 (total costs) for the initial year of
funding applications received in response to this RFA.  It
is anticipated that three to five applications will be
funded.  The award of grants pursuant to this RFA is
contingent upon the continuing availability of funds for
this purpose and upon receipt of a sufficient number of
applications of high scientific merit.
 
This RFA is a one-time solicitation.  Generally, future
unsolicited competing continuation applications will compete with
all investigator-initiated applications and be reviewed by a
Division of Research Grants study section.  However, should the
NIAID determine that there is a sufficient continuing program
need, the NIAID may announce a request for renewal applications.
 
IV.  MINIMUM REQUIREMENTS FOR APPLICATION
 
Any domestic or foreign institution, university, medical
college, hospital, or laboratory or other public, private,
or for-profit institution is eligible.  Applicants may
request up to four years of support.
 
V.  LETTER OF INTENT
 
Prospective applicants are asked to submit by March 11, 1991, a
letter of intent that includes a descriptive title and a
description (not to exceed one page) of the proposed research.
The letter of intent is requested in order to provide an
indication of the number and scope of applications to be reviewed.
The letter of intent is not
binding, nor is it a requirement for submission of an
application.  The letter of intent should be sent to:
 
      Polly R. Sager, Ph.D.
      Senior Scientist
      Developmental Therapeutics Branch
      Division of AIDS, NIAID
      6003 Executive Blvd., Room 244P
      Bethesda, MD  20892
      FAX Number:  (301) 480-5703
 
VI.  CONSEQUENCES OF LACK OF RESPONSIVENESS TO THE RFA
 
Applications that are incomplete for review or nonresponsive
to this RFA will be screened out by NIH staff upon receipt
and returned to the applicants without further
consideration.
 
VII.  REVIEW METHOD AND PEER REVIEW CRITERIA
 
Those applications that are complete and responsive may be
subjected to a triage by a peer review group to determine
their scientific merit relative to the other applications
received in response to this RFA.  The NIH will withdraw
from competition those applications judged by triage to be
noncompetitive and notify the applicant and institutional
business official.
 
Those applications judged to be competitive will be further
reviewed for scientific and technical merit by a Review
Committee convened by the Division of Research Grants, NIH.
The second level of review will be provided by the National
Advisory Allergy and Infectious Disease Council.
 
Awards will be based on scientific and technical merit,
significance, originality, adequacy of research experience,
commitment, and time availability of the Principal
Investigator and other key personnel, adequacy of
facilities, and reasonable cost.
 
VIII.  METHOD OF APPLYING
 
A.  Receipt Date
 
The deadline for receipt of applications is April 22, 1991.
Applications received after this date will be considered not
responsive to this RFA and will be returned without review.
 
B.  General
 
1.  The research grant application form PHS-398
(rev. 10/88) must be used in applying.  These forms are
available at most institutional business offices and from the
Division of Research Grants, National Institutes of Health,
Westwood Building, Room 449,
9000 Rockville Pike, Bethesda, Maryland 20892.
 
Submit a signed, typewritten original of the application,
including the Checklist, and 23 signed, exact, single-sided
photocopies, in one package to:
 
      Division of Research Grants
      National Institutes of Health
      Westwood Building, Room 240
      Bethesda, MD  20892**
 
2.  TO ASSURE THE IDENTIFICATION OF YOUR APPLICATION WITH
THIS RFA:
 
a.  The application form should have "DEVELOPMENT OF
MODELS FOR PEDIATRIC AIDS" (RFA AI-91-04) typed on
line 2 of the face page of the application form.
 
b.  The RFA label provided with the instructions must
be affixed to the bottom of the face page.  Failure to
use this label could result in delayed processing of
your application so that it may not reach the review
committee in time for review.
 
IX.  INQUIRIES
 
Additional information may be obtained from:
 
      Polly R. Sager, Ph.D.
      Developmental Therapeutics Branch
      Division of AIDS, NIAID
      6003 Executive Blvd., Room 244P
      Bethesda, MD  20892
      Telephone:  (301) 496-0636
 
This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases
Research and 93.855 - Allergy, Immunology and Transplantation
Research.  Grants are awarded under the authority of the
Public Health Service Act, Title IV, Section 301, as
amended, Public Law 78-410, Public Law 97-219, Public Law
99-158, Public Law 99-500, and Report 99-711 to accompany HR
5233 and administered under PHS grant 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.