Full Text HL-93-021

HIV AND CELLULAR INFILTRATIVE DISEASE IN THE LUNG

NIH GUIDE, Volume 22, Number 31, August 27, 1993

RFA:  HL-93-021

P.T. 34

Keywords: 
  AIDS 
  Pulmonary Diseases 
  Etiology 
  Biology, Cellular 
  Biology, Molecular 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  December 10, 1993
Application Receipt Date:  January 14, 1994

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites grant
applications for support of research on understanding cellular
infiltrative disease in the lung associated with infection by the
human immunodeficiency virus (HIV).  The primary objectives of this
special grant program are to determine the etiology of inflammatory
cell infiltration and proliferation in the lung and to understand the
cellular and molecular mechanisms involved in the development of
lymphoid and nonspecific interstitial pneumonitis associated with HIV
infection.

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 Request
for Applications (RFA), HIV and Cellular Infiltrative Disease in the
Lung, is related to the priority areas of maternal and infant health,
HIV infection, sexually transmitted diseases, and immunization and
infectious diseases.  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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Among the disciplines and expertise that may be appropriate for this
research program are cell biology, virology, molecular biology,
immunology, molecular immunology, infectious diseases, pathology, and
pulmonary medicine.

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.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) award.  Applications
from minority individuals and women are encouraged.

All current policies and requirements that govern the research grant
programs of the National Institutes of Health (NIH) will apply to
grants awarded under this RFA.  Awards under this announcement to
foreign institutions will be made only for research of very unusual
merit, need, and promise, and in accordance with PHS policy governing
such awards.

MECHANISM OF SUPPORT

The support mechanism for this program will be the NIH individual
research project grant (R01) and the FIRST award (R29).  While
multidisciplinary approaches are encouraged, it is not the intent of
this announcement to solicit applications for large studies
encompassing a variety of individual subprojects, i.e., program
projects.  If collaborative arrangements through subcontracts with
other institutions are planned, consult the program staff listed
under INQUIRIES.

Upon initiation of the program, the NHLBI will sponsor periodic
meetings to encourage exchange of information among investigators who
participate in this program.  In the budget for the grant
application, applicants should request travel funds for a one-day
meeting each year, most likely to held in Bethesda, MD.  Applicants
should also include a statement in their applications indicating
their willingness to participate in these meetings.

Applicants (who will plan and execute their own research programs)
are expected to furnish their own estimates of time required to
achieve the objectives of the proposed research project.  Up to five
years of support may be requested for R01s; five years are required
for FIRST awards.  Requested budgets for FIRST awards may not exceed
those specified in the FIRST award guidelines.  Since a variety of
approaches would represent valid responses to this announcement, it
is anticipated that there will be a range of costs among individual
grants awarded.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications may be submitted for peer review and
competition for support through the regular grant program of the NIH.
It is anticipated that support for this program will begin in July
1994.  Administrative adjustments in project period and/or amount may
be required at the time of the award.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the National Center for Research Resources
may wish to identify the GCRC as a resource for conducting the
proposed research.  If so, a letter of agreement from either the GCRC
program director or Principal Investigator should be included with
the application.

FUNDS AVAILABLE

Although approximately $1,500,000 for this program is included in the
financial plans for fiscal year 1994, award of grants pursuant to
this RFA is contingent upon receipt of funds for this purpose.  It is
anticipated that six to eight new grants will be awarded under this
program.  The specific number to be funded will, however, depend on
the merit and scope of the applications received and the availability
of funds.

RESEARCH OBJECTIVES

Background

Pulmonary disorders continue to be one of the most frequent medical
consequences of infection with HIV.  Although pulmonary infections
such as Pneumocystis carinii pneumonia, bacterial pneumonia, and
viral pneumonia represent the major portion of these disorders, a
number of interstitial infiltrative processes that cannot be directly
linked to a known infectious agent also occur frequently in
HIV-infected individuals.  Two prominent types of interstitial
processes distinguished by their clinical and pathologic features
have been recognized in association with HIV infection.

The first disorder is lymphoid interstitial pneumonitis/pulmonary
lymphoid hyperplasia complex (LIP/PLH), which is much more commonly
associated with chronic pulmonary infiltrates in HIV-infected
children than it is in HIV-infected adults.  Lymphoid interstitial
pneumonitis is characterized by infiltration of the lung by a
pleomorphic mixture of lymphocytes, plasma cells, and immunoblasts.
Although the etiology of the process is unknown, it is postulated
that it involves recognition of a specific antigen by host
lymphocytes, the activation of T-cells, increased production of
lymphokines, and a rapid increase in effector cells that is
responsible for tissue damage.  This type of lymphocytic interstitial
pneumonitis, known sometimes to accompany other disorders of the
immune system such as dysproteinemias and autoimmune diseases, was
identified early in the HIV epidemic as a common finding in
HIV-infected individuals, especially children.  Information on the
frequency with which LIP/PLH occurs is limited.  In early reports,
lymphoid interstitial pneumonitis, which is an AIDS defining
condition in children under 13 years of age, was associated with 50
to 78 percent of pulmonary complications in children with HIV
infection.  In more recent studies, LIP/PLH has been identified in 20
to 30 percent of pediatric AIDS patients.  Although benign in
individuals without HIV infection, LIP/PLH in HIV-infected
individuals may result in progressive pulmonary disease,
characterized clinically by dyspnea, cough, abnormal chest films,
hypoxemia and a restrictive defect in lung function.  Some
HIV-infected patients with LIP/PLH eventually develop lymphoid
malignancies involving the lung.

A second frequently occurring infiltrative disorder associated with
HIV infection is nonspecific interstitial pneumonitis (NIP), which is
less well characterized than LIP/PLH and occurs with equal frequency
in children and adults.  Nonspecific interstitial pneumonitis in
HIV-infected persons is characterized by lymphocyte infiltration,
interstitial edema, mononuclear cell infiltration, alveolar type II
cell proliferation, and loose interstitial fibrosis.  The prevalence
of NIP in HIV-infected individuals with pulmonary disease has been
reported to vary from 11 to 38 percent.  The lymphocytic infiltrates
characteristic of NIP are comprised mainly of CD8+ T-cells with less
than normal levels of CD4+ T-cells.  It is unclear if the latter
reflects the general diminution of CD4+ T-cells in HIV-infected
individuals or is indicative of other factors involved in its
pathogenesis.  The infiltrates of NIP are similar to those seen in
graft versus host disease and autoimmune disorders, where CD8+
T-cells also are prevalent in infiltrates.

Lymphocytes can be found in the bronchoalveolar lavage (BAL) fluid in
70 to 80 percent of HIV-infected individuals without evidence of lung
tumors or infection.  The majority of these lymphocytes are CD8+
cytotoxic T-cells which may be active against virus-infected CD4+
T-cells and thereby contribute to the depletion of CD4+ T-cells and
macrophages in the lung.  Furthermore, the CD8+ cytotoxic lymphocytes
contain significant amounts of serine protease which when released
may contribute significantly to lung tissue destruction and
subsequent morbidity.  It has been suggested that lymphocytic
alveolitis in HIV-infected adults may represent an early stage of
LIP/PLH or NIP, but this needs to be documented and the mechanism for
this process needs to be investigated.

Other

Objectives and Scope

The overall objective of this initiative is to encourage basic
research on the etiology, mechanisms of pathogenesis, and the host
determinants that are involved in the initiation and progression of
interstitial infiltrative diseases in the lung associated with HIV
infection.  Applications are invited for innovative multidisciplinary
approaches to identify the cause of these disorders and to delineate
cellular and molecular mechanisms involved in their pathogenesis.
Applications submitted in response to this announcement should
clearly define the rationale, background, and specific aims of the
proposed studies, and should provide a succinct description of the
methods and procedures to be used.  Several topics relevant to the
objectives of this RFA are cited below in order to provide a
perspective of the scope of the research that would meet the goals of
the program.  Investigators are also encouraged to consider other
approaches that meet the goals of this program in addition to those
cited below.

A.  Pathogenesis

The finding of HIV reverse transcriptase activity in bronchoalveolar
lavage fluid from HIV positive patients with LIP/PLH and correlation
of HIV activity and the presence of anti-HIV antibodies in lavage
fluid with cytopathic effects in human lung tissue from LIP/PLH
patients suggest that the infiltrative processes may be initiated by
an immunologic response to HIV infection of the lung itself.  Whether
or not HIV infection initiates these processes and how much of their
pathogenesis results from HIV infection remain to be determined.

Some investigators have suggested an interaction of HIV with other
infectious agents acting as cofactors as a major determinant in the
development and progression of the infiltrative process seen in these
disorders.  Experimental evidence for this so-called "co-factor
hypothesis" and its bearing on the pathogenesis of LIP/PLH or NIP
would be an appropriate area of study in response to this initiative.
Whether an as yet unrecognized infectious agent is responsible for
these disorders could be considered and might be pursued by
application of new approaches for identifying such agents.  For
example, electron microscopic studies of viral particles associated
with infiltrating lymphoid cells might provide insights into the type
of agent(s) which may be present.  Electron microscopy combined with
immunologic techniques (immuno-EM), which have proven useful with
other infectious diseases, could enhance such an approach.

Investigations that employ in vitro or animal models aimed at
uncovering the molecular mechanisms and pathogenesis of these
disorders are of particular interest.  It has been hypothesized that
the infiltrative processes begin as a lymphocytic alveolitis which
then progresses to either LIP/PLH or NIP.  However, there are little
or no data to support this concept.  Thus, it is of interest to
determine the relationship of lymphocytic alveolitis to these more
advanced forms of infiltrative disease and to identify the factors
that are involved in the progression to LIP/PLH and NIP.  Studies on
lymphocyte recruitment, replication, and trafficking in the lung as a
consequence of HIV infection with or without cofactors present are
needed.  Details about the types of cells that infiltrate the lung
and their state of activation relevant to the development of these
conditions are essential to understanding the mechanisms involved.
For example, does local proliferation of immune cells already present
in the lung contribute to the pathogenesis?  Identification of the
cytokines involved and their regulatory pathways in the context of
HIV infection is also needed to define the immunopathogenesis.
Investigation of the similarities and differences of infiltrative
processes in the lung in HIV-infected individuals compared to
infiltrates in other immunosuppressed states, such as graft versus
host disease, might also help to further delineate the role of HIV in
pathogenesis.

The lack of knowledge about the mechanisms contributing to the
pediatric predominance of LIP/PLH suggests a number of approaches
that could provide much needed basic information and could have
important implications for the management and treatment of children
who develop this complication.  A number of studies suggest that the
immaturity of the immune system is a factor in disease expression.
Studies are needed to provide detail about the impact of HIV
infection on the developing immune response of the lung.  Does
increased pediatric immune cell sensitivity to HIV infection which
has been demonstrated in vitro contribute to increased susceptibility
and more severe disease in these young patients?  Do growth factors
or other developmental factors which are present at higher levels in
the body during development play a role in the pathogenesis?  Are
nutritional factors important determinants in the increased
occurrence of LIP/PLH in children?

The limited clinical data available on these infiltrative processes
in the lung suggest that the course and prognosis of these diseases
is quite variable.  In several early studies, HIV-infected patients
who developed LIP/PLH or NIP were seen to progress to either end
stage fibrosis or malignancies in the lung.  It has also been noted
that black patients may be more predisposed to developing LIP/PLH
than are white patients.  Basic studies on host factors, either
acquired or genetic, that affect the expression of disease or
contribute to progression to more severe disease would be of interest
in response to this initiative.

B.  Animal Models

The ability to make significant progress in understanding the basic
mechanisms involved in these diseases would be greatly enhanced by
adaptation of this condition to animal models, especially small
laboratory animals.  While a sheep/lentivirus model is available, it
may be of limited value for studying these disorders since it does
not produce the profound immunodeficiency found in HIV infection of
humans.  Likewise the use of nonhuman primates for the mechanistic
studies sought by this initiative would likely not provide a
significant advantage over human studies.  A mouse AIDS model (MAIDS)
and rodent models for the study of opportunistic infections
associated with HIV infection have been developed and could possibly
be adapted to the study of infiltrative disease in the lung.  In
addition, the various immunologically defective laboratory animal
models that are already available might be considered for adaptation
to these studies.  Clearly, additional animal models need to be
developed and/or adapted to the study of these diseases if new
information is to be obtained about the mechanisms involved in
initiation and progression of disease.

SPECIAL REQUIREMENTS

Applications that propose descriptive studies and do not contain
studies directed at elucidating mechanisms of disease or supporting
hypotheses related to mechanisms of disease will not be acceptable.
This program will not support studies directed at development of
animal models alone.  Models must be applied to the study of disease
mechanisms associated with cellular infiltration in the lung.
Applications that focus on molecular biology and molecular immunology
of these disorders are of particular interest.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information should be included in the form PHS-398
in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.  Applicants are urged to assess carefully the
feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).  The rationale
for studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are not subject to
these policies.  However, every effort should be made to include
human tissues from women and racial/ethnic minorities when it is
important to apply the results of the study broadly, and this should
be addressed by applicants.  If the required information is not
contained within the application, the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.  NIH
funding components will not award grants or cooperative agreements
that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 10, 1993, 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 subsequent applications, the information
that it contains allows NHLBI staff to estimate the potential review
workload and to avoid conflict of interest in the review.

Chief, Centers and Special Projects Review Section
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 594-7448
FAX:  (301) 594-7407 or 594-7424

APPLICATION PROCEDURES

Submit applications on form PHS 398, (rev. 9/91), the application
form for the traditional research project grant.  This form is
available in an applicant institution's office 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) 710-0267.  Use the
conventional format for research project grant applications and
ensure the points identified in the section, "Review Procedures and
Criteria" are fulfilled.  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 "HIV and Cellular Infiltrative Disease in the Lung,"
HL-93-021-L.

The RFA label found in form PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form PHS 398.  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.

Send or deliver the completed application and three signed
photocopies in one package to:

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

Send two additional copies of the application to the Chief, Centers
and Special Projects Review Section 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.  Otherwise the NHLBI cannot guarantee that the
application will be reviewed in competition for this RFA.

Applications must be received by January 14, 1994.  If an application
is received after this date, it will be returned to the applicant
without review.  The DRG will not accept any application in response
to this announcement 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
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
DRG and responsiveness to this RFA by the NHLBI.  Incomplete
applications will be returned without further consideration.  If an
application is judged unresponsive, the applicant will be contacted
and given an opportunity to withdraw the application or to have it
considered for the regular, investigator-initiated grant program of
the NIH.

Applications judged to be responsive will be reviewed for scientific
and technical merit by an initial review group, which will be
convened by the Division of Extramural Affairs, NHLBI, solely to
review these applications.

This initial review will include a preliminary evaluation to
determine scientific merit relative to the other applications
received in response to this RFA (triage); the NIH will withdraw from
further consideration applications judged to be noncompetitive and
promptly notify the principal investigator and the official signing
for the applicant organization.  Those applications judged to be
competitive will be further evaluated for scientific/technical merit
by the usual peer review procedures.

Review Criteria.  The factors to be considered in the evaluation of
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; and the appropriateness of the
requested budget to the work proposed.

AWARD CRITERIA

The anticipated date of award is July 1, 1994.  In addition to the
scientific merit of the applications, awards will be based on
responsiveness to the RFA and the availability of resources.

INQUIRIES

Direct inquiries regarding programmatic issues to:

Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A09
Bethesda, MD  20892
Telephone:  (301) 594-7425
FAX:  (301) 594-7487

Direct inquiries regarding review matters to:

Chief, Centers and Special Projects Review Section
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 594-7448
FAX:  (301) 594-7407 or 594-7424

Direct inquiries regarding fiscal matters to:

Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17
Bethesda, MD  20892
Telephone:  (301) 594-7420
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.838.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410,
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 to review by a Health
Systems Agency.

.

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