Full Text HL-95-009

CYTOKINE EFFECTS ON HEMATOPOIESIS IN AIDS ANIMAL MODELS

NIH GUIDE, Volume 23, Number 39, November 4, 1994

RFA:  HL-95-009

P.T. 34

Keywords: 
  AIDS 
  Disease Model 
  Biology, Cellular 


National Heart, Lung, and Blood Institute (NHLBI)

Letter of Intent Receipt Date:  December 16, 1994
Application Receipt Date:  January 24, 1995

PURPOSE

The Cellular Hematology Scientific Research Group, Blood Diseases
Program, Division of Blood Diseases and Resources, NHLBI announces
the availability of a Request for Applications (RFA) on the above
subject.  The purpose of this initiative is to study animal models of
human acquired immunodeficiency syndrome (AIDS) to increase our
understanding of clinical consequences and/or efficacy of
hematopoietic factors used in HIV-1 infected persons.  The complexity
of HIV disease makes it difficult to assess cytokine effects
exclusively in the patient.  Thus, this initiative will primarily
focus on animal models of human AIDS that could be directly related
to future human clinical studies.  However, focused cytokine studies
in HIV-1 infected persons will be considered.

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
initiative, Cytokine Effects on Hematopoiesis in AIDS Animal Models,
is related to the priority area of HIV infection.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-782-3238).

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 or local
governments, and eligible agencies of the Federal government.  Awards
in response to this RFA will be made to foreign institutions only for
research of very unusual merit, need, and promise, and in accordance
with PHS policy governing such awards.  Foreign institutions are not
eligible for First Independent Research Support and Transition
(FIRST) (R29) awards.  Applications from minority individuals and
women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) award and is a one-time
solicitation.  Applicants, who will plan and execute their own
research programs, are requested to furnish their own estimates of
the time required to achieve the objectives of the proposed research
project.  Up to five years of support may be requested.  At the end
of the official award period, renewal applications may be submitted
for peer review and competition for support through the regular grant
program of the NHLBI.  It is anticipated that support for the present
program will begin in August 1995.  Administrative adjustments in
project period and/or amount of support may be required at the time
of the award.  All current policies and requirements that govern the
research grant programs of the NIH will apply to grants awarded in
response to this RFA.

FUNDS AVAILABLE

Fiscal Year 1995 financial plans for the NHLBI include $1.5 million
for this program.  However, award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.  It is anticipated
that the NHLBI will award approximately six new grants under this
program.  The specific amount to be funded will, however, depend on
the merit and scope of the applications received and on the
availability of funds.  Since a variety of approaches would represent
valid responses to this RFA, it is anticipated that there will be a
range of costs among individual grants awarded.  If collaborative
arrangements involve sub-contracts with other institutions, the NHLBI
Grants Management Staff (tel: 301-594-7436) should be consulted
regarding procedures to be followed.  Designated funding levels
are/or project period duration are subject to change at anytime due
unforeseen budgetary administrative and/or scientific developments.

RESEARCH OBJECTIVES

AIDS remains among the most important public health challenges in the
United States and abroad.  The disease has managed to affect every
segment of the population including the fetus and the newborn.
Current estimates of HIV-1 prevalence place the number of HIV-1
infected individuals around one million.  Early this fall, the
Centers for Disease Control plans to release a new estimate of the
prevalence of HIV-1 infection in the United States.

The natural history of HIV infection is characterized by an abundance
of hematologic complications. Anemia is the most frequent abnormality
and is manifest at presentation in up to 20 percent of patients.  By
end-stage disease, 75 to 100 percent of patients become anemic (1,2).
Thrombocytopenia and diminished marrow production are seen throughout
all stages of AIDS.  Leukopenia, consisting of monocytopenia.
neutropenia, and lymphopenia, correlates with the stage of disease
and as seen in anemia, is worsened with azidothymidine (3).
Zidovudine, trimethoprim sulfamethoxazole, and ganciclovir all can
produce or contribute to cytopenias.  Reduced marrow reserves and
cytopenias complicate treatment for not only HIV but also HIV related
malignancies and opportunistic infections.

The past decade has witnessed the cloning and characterization of
multiple hematopoietic growth factors and cytokines.  As a result,
cytokines have been used clinically in HIV-1 infection to treat
persons with HIV-related cytopenias resulting in improved management
of these complications.  Although cytokines have generally been well
tolerated in clinical use, a number of important questions still
remain regarding their use in HIV-1 infected individuals.

Granulocyte macrophage colony stimulating factor (GM-CSF) and
granulocyte colony stimulating factor (G-CSF) are very frequently
used to manage HIV-1-related neutropenia.  In phase I trials, GM-CSF
has produced an increase in peripheral neutrophils and eosinophils
and a slight rise in monocytes when it was administered to
individuals with AIDS-related neutropenia (4,5).  Although some
investigators have reported that neutrophil function improves in
these patients (6), others have reported that neutrophils released
from the bone marrow after administration of the drug are
dysfunctional (7).  Also of some concern to clinicians, is the
demonstration that in vitro, GM-CSF potentiates HIV-1 replication
(8,9).

G-CSF has also been used in the treatment of individuals with HIV-1
infection.  Unlike GM-CSF, G-CSF has not been shown to increase the
activity of HIV-1 in monocytes and macrophages (10) and also elicits
fewer toxicities than GM-CSF (11).  Although G-CSF has been shown to
increase circulating neutrophils in patients with HIV infection (12),
it is not clear if this response translates into fewer infections or
increased survival.  Other cytokines including M-CSF and
interleukin-3 (IL-3) have also been characterized, but few studies
detail their clinical use. M-CSF induces proliferation of mononuclear
cells and has been shown to potentiate the infection of HIV-1 (13).
Additionally, IL-3 has been shown to stimulate multiple hematopoietic
cell lines (14), but it too has been associated with an increase in
HIV proliferation in vitro by infected macrophages and monocytes.
Alpha interferon has been reported to have an anti-viral effect when
administered to individuals with HIV infection (15).

Important questions still remain regarding the use of cytokines in
HIV-1 infected individuals.  Cytokine effects on hematopoietic cells
and stromal elements have been primarily demonstrated in vitro with
very little information available about their effects in vivo.  Since
these factors typically have multiple actions, some of these actions
may be undesirable in a given case.  In fact, when one gives a single
factor, no less than three general events occur:  (a) the blood level
of the factor increases and the biological activity of that factor is
exerted; (b) the factor induces auxiliary cells to release other
cytokines; and (c) the administered factor will act synergistically
with at least some of the endogenous factors it induces.  Thus, the
current view that hematopoietic growth factors simply stimulate the
production of more white cells or the proliferation and/or
differentiation of stem/progenitor cells, may inappropriately
trivialize the physiologic events that take place in HIV-1 infected
individuals when cytokines are administered.

The many and complex opportunistic infections, neoplasms, and drug
treatments, both prophylactic and active, make it difficult to
unravel the pathogenesis of HIV disease.  These phenomena
significantly contribute to the difficulties in assessing the
advantages and disadvantages of the use of cytokines in AIDS
patients.  Therefore, to gain insight into this important area, this
RFA will focus primarily on the use of animal models of human AIDS.
Recently, studies have demonstrated differences between the levels of
viral burden and virus replication in peripheral blood versus
lymphoid organs (16).  Animal models could potentially provide a
unique opportunity to assess these differences with larger numbers
and to determine the impact of the use of cytokines on virus
replication.  In addition, animal models will undoubtedly continue to
prove useful for studies of anti-HIV gene therapy strategies.  The
utility of animal models to study the pathogenesis of AIDS has been
extensively reviewed (17,18).

This RFA encourages applications that propose studies designed to
better assess the use of hematopoietic factors in HIV-1 infected
individuals.  The primary focus of this RFA is to conduct the above
assessment in animal models of human AIDS.  The proposed studies
should be directly related to evolution to future human clinical
studies.  Moreover, in vitro studies proposed should have an in vivo
endpoint.  Also, recent PCR technology would allow focused cytokine
studies to be conducted in HIV-1 infected persons.  Therefore,
appropriate studies assessing the effects of cytokines in HIV-1
infected individuals will be considered.  Research approaches that
would be considered responsive to the program would include studies
to (a) develop new animal models of human AIDS to better assess
cytokine use in HIV-1 infected persons; (b) evaluate the effect(s) of
cytokines used clinically in HIV-1 infected persons on viral burden,
viral persistence, and viral infectivity of stem/progenitor cells and
stromal elements; (c) evaluate the interplay of exogenously added
cytokines and endogenous cytokines induced by HIV infection; (d)
assess the different compartments of HIV-1 virus replication (i.e.,
peripheral blood vs. lymphoid tissue) and determine the impact of the
use of cytokines on viral replication; and (e) evaluate the effects
of cytokines on potential anti-HIV gene therapy treatment approaches
(i.e., genetically altered stem/progenitor cell transplantation).

The above examples of research approaches are not meant to be all
inclusive or restrictive.  Investigators are encouraged to develop
their own innovative approaches to achieve the goals of this
initiative.

Exclusions

Epidemiological studies, large-scale clinical trials, and large
multi-project grant applications (program project grants) are
specifically excluded from this RFA.  Also, research focused on
testing the effectiveness of vaccines for HIV infection is excluded.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor annual
meetings to encourage an exchange of information among investigators
who participate in this program.  In preparing the budget for the
grant application, applicants should request additional travel funds
for one meeting each year to be held in Bethesda, Maryland.
Applicants should also include a statement in the application
indicating their willingness to participate in such meetings.

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 new
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 of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 16, 1994, 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.  Such letters are requested
only for the purpose of providing an indication of the number and
scope of applications to be received; therefore their receipt is
usually not acknowledged.  A letter of intent is not binding, it will
not enter into the review of any application subsequently submitted,
nor is it a necessary requirement for the application.

This letter of intent is to be sent to:

Dr. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 557A
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407
Email:  James_Scheirer@NIH.Gov

APPLICATION PROCEDURES

Application Receipt Date:  January 24, 1995

Applications are to be submitted on the research grant application
form PHS 398 (rev. 9/91).  This form is available in at most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 435-0714.  Use the conventional format for research
project grant applications and ensure that the points identified in
the section REVIEW CONSIDERATIONS are fulfilled.  FIRST applications
must include at least three sealed letters of reference attached to
the face page of the original application.  FIRST applications
submitted without the required number of reference letters will be
considered incomplete and will be returned without review.

The RFA label available in the PHS 398 application kit must be
affixed to the bottom of the face page of the original copy 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.  To identify the application as a
response to this RFA, check "YES" on Item 2a of page 1 of the
application and enter the title and RFA Number:  CYTOKINE EFFECTS ON
HEMATOPOIESIS IN AIDS ANIMAL MODELS RFA HL-95-009.

Send or deliver the completed application and three signed, exact
photocopies of it to the following, making sure that the original
application with the RFA label attached is on top:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send an additional two copies of the application to the Chief, Review
Branch at the address listed under LETTER OF INTENT.  It is important
to send these two copies at the same time as the original and three
copies are sent to the Division of Research Grants (DRG).  Otherwise
the NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by January 24, 1995.  An application
not received by this date will be returned to the applicant without
review.  The DRG 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
DRG will not accept any application that is 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.

Although this is an RFA from the NHLBI, the National Institute of
Allergy and Infectious Diseases (NIAID) and the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) also have an
interest in research focused on the role of cytokines in AIDS and the
development of AIDS animal models.  In addition, the National Cancer
Institute (NCI) has an interest in the role of cytokines in AIDS
pathogenesis particularly, in the development of AIDS- associated
malignancies.  Therefore, the NIAID, the NCI or the NIDDK may be
given an institute assignment in accordance with NIH referral
guidelines.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness and
responsiveness by the National Institutes of Health (NIH).
Incomplete applications and applications deemed not responsive to the
RFA 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 the NHLBI in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator/program director
and the official signing for the applicant organization will be
promptly notified.

The criteria used in evaluating the scientific merit of each
application will be similar to those used in the review of
traditional research-project grant applications, including the
novelty, originality, and feasibility of the approach; the training,
experience and research competence of the investigator(s); the
adequacy of the experimental design; the suitability of the
facilities; the appropriateness of the requested budget to the work
proposed; and the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research.

Applications should be prepared so that they can be reviewed without
the necessity of interaction between applicants and reviewers since
no site visit or reverse site visit will be part of the technical
merit review.

AWARD CRITERIA

The anticipated date of award is August 1995.  Funding decisions will
be made on the basis of scientific and technical merit as determined
by peer review, program needs and balance, and the availability of
funds.

Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.  Designated funding
levels are subject to change at any time prior to award, due to
unforeseen budgetary, administrative and/or scientific developments.

In order to more evenly distribute administrative workload and reduce
the number of awards with July 1 or September 30 start dates, the
NHLBI will award ten months of time and money for the first competing
budget period of this project.  This action results in a project
period of 58 months rather than 60 months for R01 applications.
Investigators should plan their research projects and budgets within
these timeframes.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Helena O. Mishoe, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5A12
Bethesda, MD  20892
Telephone:  (301) 496-5911
FAX:  (301) 496-9940
Email:  Helena_Mishoe@NIH.Gov

Direct inquiries regarding fiscal matters to:

Ms. Jane R. Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7436
FAX:  (301) 594-7492
Email:  Jane_Davis@NIH.Gov

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of Federal Domestic Assistance number
93.839.  Awards are made under the authority of the Public Health
Service Act, Section 301 (42 USC 241) and administered under PHS
grant policies and Federal regulations, most specifically 42 CFR Part
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.

References

1.  Spivak JL, Bender BS, Quinn TC. Hematologic abnormalities in the
acquired immune deficiency syndrome. Am J Medicine 77:224-228, 1974.

2.  Zon, LI, Arkin C, Groopman JE. Hematologic Manifestations of
human immune deficiency virus (HIV). Br J Haematol 66:251-256, 1987.

3.  Fischl MA, Ricnman DD, Hansen N, Collier AC, Carey JT, Para MF,
Hardy D. Dolin R. Powderly WG, Allan JD, Wong B, Merigan TC,
McAuliffe VJ, Hyslop NE. Rhame FS, Balfour HH, Spector SA, Volberdino
P, Pettinelli C, Anderson J. The safety and efficacy of zidovudine
(AZT) in the treatment of subjects with mildly symptomatic human
immunodeficiency virus type 1 (HIV) infection.  Annals Internal Med
112:727-737, 1990.

4.  Groopman JE, Granulocyte-macrophage colony-stimulating tor in
human immunodeficiency virus disease. Semin Hematol 27:8-14, 1990.

5.  Groopman JE, Mitsuyasu RT, DeLeo MY, et al. Effect of recombinant
human granulocyte-macrophage colony-stimulating factor on
myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med
317:533-598, 1987.

6.  Baldwin GC, Gasson JC, Quan SG, et al. Granulocyte-macrophage
colonystimulating factor enhances neutrophil function in acquired
immunodeficiency syndrome patients. Proceedings of the National
Academy of Sciences of the USA 85:2763-2766, 1988.

7.  Peters WP, Stuart A, Affronti MI, Kim KS, Coleman R. Neutrophil
migration is defective during recombinant GMCSF infusion after
autologous bone marrow transplantation in humans. Blood 72:1310-1315,
1988.

8.  Perno CF, Yarchoan R, Cooney DA, et al. Replication of human
immunodeficiency virus in monocytes; granulocyte/macrophage
colonystimulating factor (GM-CSF) potentiates viral production yet
enhances the antiviral effect mediated by
3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside
congeners of thymidine. J Exp Med 169:933-951, 1989.

9.  Pluda JM, Yarchoan R, Smith PD, et al. Subcutaneous recombinant
granulocyte-macrophage colony-stimulating factor used as a single
agent and in an alternating regimen with azidothymidine in leukopenic
patients with severe human immunodeficiency virus infection. Blood
76:463-472, 1990.

10.  Koyanagi Y, O'Brien WA, Zhao JQ. Cytokines alter production of
HIV-1 from primary mononuclear phagocytes. Science 241:1673-1675,
1988.

11.  Davey RT, Davey V, Zurol J. A phase I/II trial of zidovudine
interferon alpha and granulocyte-macrophage colony stimulating factor
in treatment of HIV infection. 6th Int Conf on AIDS, San Francisco,
June 11-24, 1990.

12.  Miles SA, Milsuyasu R, Fink N. Recombinant G-CSF and recombinant
erythropoietin may abrogate the neutropenia and anemia of AIDS and
allow resumption of AZT. 5th Int Conf on AIDS, Montreal, June 4-9, p.
550, 1989.

13.  Perno CF, Yarchoan R, Cooney DA, et al. Differential modulation
of HIV replication and AZT activity in monocyte/macrophages by GM-
CSF, M-CSF, G-CSF. 5th Int Conf on AIDS, Montreal, June 4-9, p. 536,
1989.

14.  Alter R, Welniak LA, Jackson JD, Garrison L, Weisenburger DD,
Kessinger, A. In vitro clonogenic monitoring of peripheral blood stem
cell collections following interleukin-3 administration. Blood 76(10)
Supplement 1:129a, 1990.

15.  Lane HC, Davey V, Kovacs JA, et al. Interferon-alpha in patients
with asymptomatic human immunodeficiency virus (HIV) infection. Ann
Intern Med 112:805-811, 1990.

16.  Pantaleo G, Grazios C, Demarest JF, Butini L, HIV infection is
active and progressive in lymphoid tissues during the clinically late
stage of the disease. Nature 362(6418): 355-358, 1993.

17.  Fultz P. Nonhuman primate models for AIDS. Clinical Infectious
Diseases 17 (suppl 1): S230-S235, 1993.

18.  Letvin, N. Animal models for the study of human immunodeficiency
virus infections. Current Opinions in Immunology 4:481-485, 1992.

.

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