RESEARCH ON THE HEMATOLOGIC ABNORMALITIES IN AIDS

Release Date:  July 9, 1998

PA NUMBER:  PA-98-088

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Allergy and Infectious Diseases
National Heart, Lung, and Blood Institute
National Cancer Institute

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the
National Institute of Allergy and Infectious Diseases (NIAID), the National
Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institute (NCI)
invite grant applications for support of research addressing fundamental
questions of hematologic abnormalities exhibited by humans infected by Human
Immunodeficiency Viruses (HIV), the infectious agents of Human Acquired
Immunodeficiency Syndrome (AIDS). Hematologic abnormalities in patients with the
HIV infection are common.  These abnormalities can have a significant impact on
the course of treatment for these patients.

Fundamental progress has been made in understanding the molecular biology and
clinical aspects of retroviral infection.  It has become clear that further
studies of retroviral-induced neoplasms of immunodeficiency states will continue
to provide useful new information about the cellular and humoral basis of the
immune responses, including the mechanisms leading to hematologic abnormalities
which are seen following HIV infection.  This program announcement (PA) is
intended to solicit applications for support of studies on the cellular basis of
these hematologic abnormalities.

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.  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, 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) individual research
project grant (R01) award mechanism.  Responsibility for planning, direction, and
execution of the proposed project will be solely that of the applicant.  Because
the nature and scope of the research proposed in response to this PA may vary,
it is anticipated that the size of an award will vary also.

RESEARCH OBJECTIVES

The objective of this program announcement is to solicit applications in which
the hematologic abnormalities seen following HIV infection are examined at the
cellular and molecular level.  Particular encouragement is offered to
investigators who are well trained in the modern techniques of cell biology and
molecular biology who currently may be pursuing other research interests. 
Investigators with interdisciplinary and collaborative arrangements already in
place are encouraged to respond to this program announcement.  Applications
should be focused on issues directly relevant to the understanding of the
pathogenesis of cytopenia following HIV infection, and the role of hematopoietic
precursor cells in the development of AIDS.  Such studies, and findings emerging
thereof, are also expected to lead to the development of new treatment strategies
and clinical protocols.  The following descriptions of the types of areas that
may be appropriate to study are provided for illustrative purposes only and are
not meant to be all-inclusive or restrictive.

Numerous hematologic abnormalities arise in individuals following HIV Infection,
many of which may cause life-threatening symptoms or may impair the quality of
life of these patients.  Understanding how these abnormalities arise may be
complicated by a variety of other infections, in addition to HIV, which usually
are seen in these patients.  Bone marrow dysplasia, anemia, thrombocytopenia, and
leukopenia occur frequently in patients with HIV infection.  Both ineffective
hematopoiesis and peripheral destruction of blood cells may lead to cytopenia
common in AIDS patients.  The latter condition may be due to accelerated
utilization and destruction of cells due to opportunistic infections,
reticuloendothelial cell dysfunction, or to specific autoimmunity.  Ineffective
hematopoiesis in patients with AIDS has several potential causes which may
include, for example: (1) Suppression of the bone marrow by the HIV infection
through abnormal cytokine expression and alteration of the bone marrow
environment; (2) the formation of circulating inhibitors; and (3) the effects of
HIV on hematopoietic stem cells.  The recent development of new technologies to
make recombinant human hematopoietic growth factors has made it possible to
correct some of the cytopenias associated with HIV infection and has also
fostered studies of the role of growth factors in hematopoiesis, both in vitro
and in vivo.

Thrombocytopenia is seen in HIV infected patients with a high degree of
incidence, and immune thrombocytic purpura has been recognized as a diagnostic
category of the AIDS-Related Complex (ARC).  The development of thrombopenia in
HIV infections appears to be similar to that of other forms of idiopathic
thrombocytopenic purpura.  Antibody production against a 25,000 dalton protein
of platelet membrane origin has been postulated to have a resemblance to an HIV
precursor protein and may be involved in the formation of immune complexes which
result in platelet destruction.  Platelet transfusions sometimes are needed for
the treatment of thrombocytopenia caused by decreased platelet production. 
Thrombocytopenia in HIV infected persons is an important clinical condition
associated with shortened survival.  Anemia is frequently present in HIV patients
and its origin is unknown.  The lack of reticulocyte response seen in these
patients may be due to a hypoproliferative anemia or to ineffective
hematopoiesis.  Low erythropoietin levels and associated abnormalities seen in
some AIDS patients may be a contributing factor to anemia.  Supportive care for
anemia includes the use of erythropoietin in addition to the judicious use of red
blood cell transfusion.

Neutropenia in AIDS patients is common.  The recombinant human growth factor GM-
CSF has been used in some clinical trials with AIDS patients and has been found
to ameliorate the neutropenia of AIDS as well as that induced by treatment with
zidovudine.  Current therapy for neutropenia includes the use of the myeloid
growth factors G-CSF and GM-CSF.

Treatment of cytopenias has been revolutionized by the development of
hematopoietic growth factors and although it is not clear whether or not growth
factors significantly change the morbidity of HIV-1 infection, they do ameliorate
the associated leukopenia and anemia.  The effect of long term administration of
growth factors with cytotoxic agents is not known.  Appropriate treatment of
thrombocytopenia is controversial.  Although steroids are effective in increasing
the platelet count in 60-80% of cases, there is concern that they may lead to
further immunosuppression and may adversely affect the course of Kaposi's
sarcoma.  The newly identified thrombopoietin has not been tested clinically in
HIV-infected individuals, so its effectiveness is not known.

Human hematopoietic progenitor stem cells represent a major potential
transplantation resource, as therapy for malignancy, or in immunologic diseases,
and are principal targets for gene therapy in the treatment of genetic diseases. 
However, much more needs to be learned about the biology of stem cells and their
progenitors including dendritic cells, and the microenvironment (bone marrow and
thymic stroma, lymph nodes, spleen, and the cytokine repertoire) in which they
are maintained, differentiate, and mature, before these cells can be used
routinely for immune reconstitution and gene therapy for AIDS.  There have been
numerous reports of retrovirus mediated gene transfer in murine and in vitro
models, but results of attempts at retroviral gene transfer into human long-term
repopulating stem cells have been disappointing.  The inefficiency of
transduction using human stem cells in these studies has been too low to expect
any clinical benefit to AIDS patients given current efficiencies.  Research
studies to address these issues are essential.

Applications for support of clinical studies in humans are not sought at this
time.  In addition, the following studies would not be considered appropriate for
this program announcement: (1) studies that do not emphasize the cellular and
molecular basis of abnormal hematopoietic differentiation in AIDS; (2) general
studies on hematopoiesis; and (3) phenomena associated with hematopoiesis in
various disease states not related to AIDS.

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 is provided 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
"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 in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators may obtain copies of the policy from the program staff listed under
INQUIRIES.  Program staff also may 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://www.nih.gov/grants/guide/notice-files/not98-024.html.

ANIMAL WELFARE CONSIDERATIONS

Investigators are encouraged to consider alternative methods and approaches in
their research grant applications that do not require the use of whole animals,
use alternative species such as non-mammals or invertebrates, reduce the number
of animals required, and incorporate refinements to procedures that will result
in the elimination or further minimization of pain and distress in animals.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated in
the application kit.  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 301-710-0267, email:
grantsinfo@nih.gov.

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

The completed original application and five legible copies must be sent or
delivered 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 Public Health Service
referral guidelines.  Applications that are complete will be evaluated for
scientific and technical merit by an appropriate peer review group convened in
accordance with 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.  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 also will 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.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  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:

David G. Badman, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13C MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  David_Badman@nih.gov

Nava Sarver, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C01
Bethesda, MD  20892-7620
Telephone:  (301) 496-2970
FAX:  (301) 402-3211
Email:  ns18p@nih.gov

Helena O. Mishoe, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10156
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 480-0868
Email:  hm31y@nih.gov

John F. Finerty, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 513
Bethesda, MD  20892-0001
Telephone:  (301) 496-7815
FAX:  (301) 402-1037
Email:  fin@nih.gov

Inquiries regarding fiscal matters may be directed to:

Ms. Donita Marconi
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8860
Email:  dm150h@nih.gov

Ms. Mollie Shea
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B26
Bethesda, MD  20892-7610
Telephone:  (301) 402-6576
FAX:  (301) 480-3780
Email:  ms256g@nih.gov

Ms. Jane R. Davis
Grants Management Office
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7174-C, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  jane_davis@nih.gov

Mr. Leo Buscher
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 234
Bethesda, MD  20892-7150
Telephone:  (301) 496-7753
FAX:  (301) 402-3409
Email:  buscherl@gab.nci.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.849, 93.856, 98.839, and 93.396.  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.

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 PHS mission to protect
and advance the physical and mental health of the American people.

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