Full Text HL-96-008
 
REGULATION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) ACTIVATION IN THE
LUNG
 
NIH GUIDE, Volume 25, Number 4, February 16, 1996
 
RFA:  HL-96-008
 
P.T. 34

Keywords: 
  AIDS 
  Biology, Cellular 
  Respiratory System 
  Pulmonary Diseases 

 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  April 23, 1996
Application Receipt Date:  June 11, 1996
 
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS RFA
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS
RFA.
 
PURPOSE
 
The National Heart, Lung, and Blood Institute (NHLBI) invites
research grant applications for support of research on the regulation
of activation of HIV in the lung and mechanisms by which co-factors
may lead to increased HIV-associated pulmonary disease.  The primary
objectives of this special grant program are to understand the
cellular and molecular mechanisms involved in activation of HIV in
lung cells and the subsequent effects this has on the course of HIV
disease, especially in the lung.  Among the disciplines and expertise
that may be appropriate for this research program are virology,
molecular biology, cell biology, immunology, molecular immunology,
infectious diseases, pathology, pulmonary medicine, and pediatrics.
 
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), Regulation of Human Immunodeficiency Virus
(HIV) Activation in the Lung, is related to the priority area of
immunization and infectious diseases.  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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
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 RFA 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
 
This RFA will use the NIH individual research project grant (R01) and
the First Independent Research Support and Transition (FIRST) award
(R29) mechanisms of support.  Specific application instructions have
been modified to reflect the "MODULAR GRANT" and the FIRST (R29)
award requirements.  They will BOTH incorporate the "JUST-IN-TIME"
streamlining efforts being developed by the NIH.
 
Multidisciplinary approaches are encouraged, but it is not the intent
of this RFA 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.
 
Streamlining features of applications for both the R01 or R29
mechanisms are as follows:
 
Instructions for completing the Biographical Sketch have been
modified.  In addition, Other Support information and the application
Checklist page are not required as part of the initial application.
If there is a possibility for an award, necessary budget, other
support and checklist information will be requested by NHLBI staff
following the initial review.  The APPLICATION PROCEDURES section of
this RFA provides specific details of modifications to standard PHS
398 application kit instructions.
 
Applicants are expected to furnish their own estimates of time
required to achieve the objectives of the proposed research project.
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. Up to five years of support may be
requested on R01 applications.  FIRST award applications must request
five years of research support.
 
This RFA is a 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.  It is anticipated that support for
this program will begin in September 1996.  Administrative
adjustments in project period and/or amount may be necessary at the
time of the award.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH 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.
 
The National Institute of Allergy and Infectious Diseases (NIAID)
also has interest in regulation of HIV activation.  Therefore,
applications that are of mutual interest are likely to be given a
secondary assignment to NIAID in accordance with the NIH referral
guidelines.
 
FUNDS AVAILABLE
 
It is anticipated that for fiscal year 1996, approximately $2,000,000
total costs will be available for the first year of support for this
initiative.  Award of grants pursuant to this RFA is contingent upon
receipt of such funds for this purpose.  It is anticipated that as
many as eight new grants may be awarded under this program.  The
specific number to be funded will, however, depend on the merit and
scope of the applications received and on the availability of funds.
Direct costs for R01 applications will be awarded in modules of
$25,000, less any overlap or other necessary administrative
adjustments.  FIRST Awards (R29) will be awarded according to the
standard program guidelines, i.e., five years, $350,000 maximum
direct costs with no single budget period to exceed $100,000, and no
less than a 50 percent commitment from the Principal Investigator,
less any overlap or other necessary administrative adjustments.
 
All Indirect costs will be awarded based on the negotiated rates.
 
RESEARCH OBJECTIVES
 
Background
 
The AIDS epidemic continues to spread and pulmonary disease
associated with HIV infection continues to be a major cause of
morbidity and mortality.  Although it has been demonstrated that
cells in the lower respiratory tract can contain virus early after
HIV infection begins, pulmonary complications in HIV infected
individuals seem to occur later in the disease process.  HIV proteins
can be demonstrated in the lungs of patients with AIDS as well as in
HIV seropositive subjects without respiratory symptoms.  The
mechanisms which may lead to the activation or continued quiescence
of HIV in the lung have not been clearly defined. Several factors,
both intrinsic to the virus and external, have been proposed to
influence the activation of HIV in the lung.  Intrinsic viral factors
include viral tropism and ability to produce certain gene products
that may affect viral replication in lung macrophages (e.g., vpr gene
product).  External influences include concurrent bacterial and viral
infections, environmental exposures, hormones and cytokines and their
networks.  In vitro systems have shown that macrophages latently
infected with HIV can be stimulated to produce infectious virus by
exposure to phorbol esters, cytokines such as interleukin 1,
interleukin 6, TNF-alpha, TNF-beta, GM-CSF, mitogens, endotoxin, and
other viruses.  Concurrent HIV and cytomegalovirus (CMV) infections
have been noted in the brain at sites which show the greatest areas
of inflammation and the highest concentration of HIV infection,
suggesting CMV may be an important cofactor in HIV related disease
processes.  Dual infections with HIV and CMV are common in the lung,
appear to affect the function of the alveolar macrophages, and may
influence the progression of HIV disease.
 
Macrophages located in the lung may play a very important role as a
reservoir in that they can harbor HIV for long periods of time.  This
may be important, not only in the context of  HIV-associated lung
disease, but also for understanding the temporal expression of
systemic HIV disease.  Lung macrophages are known to be major
producers of cytokines thought to activate HIV replication.  In turn,
HIV infection either alone or in the presence of other viruses has
been shown in vitro to influence regulation of cellular function
including cytokine production and accessory cell function.  The
effect of concurrent viral infection on the regulation of cellular
function may also play an important role in the activation of HIV in
the lung.  The implications of this need to be defined in greater
detail.  Co-factors such as viral infections, cytokines, and
environmental factors may enhance the ability of HIV to stimulate
macrophages to produce cytokines, which in turn can up regulate HIV
infectious processes.  Non-viral co-factors that appear to enhance
growth of HIV in vitro include pneumonias caused by Mtb, other
bacteria or P. carinii, and cigarette smoke.  Epidemiological data
are consistent with this hypothesis in that HIV infected subjects who
are cigarette smokers or who have active TB appear to do less well
with their HIV infection than those who are nonsmokers or those
without TB.  Some co-factors may be unique in the lung due to the
constant exposure to environmental stimuli.  This is an area that is
almost totally unexplored.  Applications submitted in response to
this RFA should focus on mechanisms by which the risk
factors/co-factors, operating in the lung, lead to enhanced pulmonary
disease and may also address how this may lead to the accelerated
progression of HIV disease.
 
Objectives and Scope
 
The objective of this program is to elucidate mechanisms that
activate HIV or allow the virus to remain in a quiescent state in
pulmonary cells.  These might include studies of viral, cellular, and
immunological interactions, especially interactions at the molecular
level, that affect activity of HIV in the lung.
 
Examples of areas of research that might be included under this RFA
are as follows:
 
o  determine mechanisms whereby specific cytokines permit or prevent
activation of HIV in the lung;
 
o  determine the course and effects of  activation of HIV in lung
cells, via cytokine networks, and the extent to which this can be
manipulated without interfering with essential cellular functions;
 
o  investigate factors within the viral genome that affect the course
of viral activation and replication within lung cells;
 
o  examine genetic factors within the host lung cells that control
activation of virus;
 
o  elucidate specific pathways whereby co-infection with other
microorganisms, e.g., CMV, mycobacteria, Pneumocystis carinii,
Streptococcus pneumoniae, and exposure to their products alters
activation of HIV;
 
o  elucidate specific pathways and mechanisms related to activation
of HIV by environmental exposures, e.g., cigarette smoke;
 
o  determine mechanisms of hormonal effects on activation of HIV.
 
These are examples only.  Investigators are not feel limited to the
subjects mentioned above and are encouraged to submit other topics
pertinent to the objectives of the RFA.
 
This initiative may involve studies in human subjects, as well as
investigations using animal models or in vitro systems.  The
initiative is relevant to black and Hispanic minority populations who
are disproportionately affected by HIV in comparison to the total
population.
 
SPECIAL REQUIREMENTS
 
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 be held in Bethesda, Maryland.
Applicants should also include a statement in their applications
indicating their willingness to participate in these meetings.
 
Applications that propose descriptive studies and do not contain
hypothesis driven studies directed at understanding the mechanisms
and consequences of activation of HIV in the lung will not be
acceptable.  This program will not support studies directed at
development of animal models alone.  The models must be used to study
regulation and effects of activation of HIV in lung cells.
Applications that focus on these mechanisms at the molecular level
are of particular interest.
 
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
follow 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 also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by April 23, 1996, 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 NIH staff to estimate the potential review
workload and to avoid conflict of interest in the review.
 
The letter of intent is to be mailed or faxed, to:
 
C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email: james_scheirer@nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
from the Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714,
email:  girg@drgpo.drg.nih.gov; and from Monique Rush at the address
listed under INQUIRIES.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
The RFA label found in the PHS 398 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.
 
R01 grants under this RFA will be awarded as modular grants.  The
modular grant concept establishes specific modules (increments) in
which direct costs may be requested and a maximum level for requested
direct cost.  Only limited budgetary information is required in the
application; a detailed budget need not be provided.  The R01
application must request funds in $25,000 direct cost modules and a
maximum of eight modules ($200,000 direct cost) per year may be
requested.  No escalation is provided for future years; all
anticipated expenses for all years of the project must be included
within the number of modules per year being requested.  Any budget
adjustments made by the Initial Review Group will be in modules of
$25,000.
 
FIRST (R29) applications submitted in response to this RFA are
subject to the current FIRST award guidelines (DRG FIRST Award
Guidelines, February 1994).  This includes the requirement that FIRST
Awards request five years of support not to exceed $350,000 direct
costs for the entire project period and no more than $100,000 be
requested in any one budget period.  Include all letters of
recommendation as outlined in the FIRST Award guidelines.  The
Principal Investigator must commit a minimum of 50 percent effort to
the project.  A detailed budget request should NOT be provided in the
application.  However, the anticipated level of effort (50 percent or
greater) in all years and a brief description of responsibilities for
the Principal Investigator and all key personnel must be specifically
stated.  The applicant should also include a narrative justification
for any other budget items that are requested for the conduct of the
project.  No specific costs for items or categories are required.
 
The following modifications are made to the standard PHS 398
application instructions:
 
o  INITIAL BUDGET PERIOD
 
R01 APPLICATIONS:
 
For R01 applications, no Form Page 4 is required and no categorical
dollar information should be provided.  The total direct cost must be
requested in increments of $25,000.  Applicants may not request a
change in the amount of each module.  A maximum of eight modules
($200,000 direct cost) per year may be requested.  The exact cost of
each budget item requested is not to be provided.  However, the
budget must be justified on Form Page 5.  The budget justification
should include the following:
 
o  The names, role, and their percent of effort on the project for
all project personnel.
 
o  A narrative justification for any major budget item other than
personnel (i.e., equipment or a major resource) that is requested
 
o  If sub-contracts are involved, state the name(s) of collaborating
institutions and provide individual budgets (Form Page 5) as
described in the "SUB-CONTRACTS" section below.
 
R29 APPLICATIONS:
 
FIRST (R29) Award applicants need not submit detailed budget
requests.  The names of all project personnel, their role on the
project, and their percent effort should be presented in a narrative
justification on Form Page 4.  In addition, applicants should provide
a narrative justification, beginning on Form Page 5, for the
significant resources requested for the conduct of project (i.e.,
equipment).  FIRST (R29) Award applicants are limited to $100,000 in
any one budget period and may not exceed the overall maximum of
$350,000 for the entire project period in accordance with the FIRST
(R29) guidelines.
 
Please note that for both the R01 or the R29 application, any large
one-time purchases, such as large equipment requests, must be
accommodated within these limits.  Applications not conforming to
these guidelines will be considered unresponsive to this RFA and will
be returned without further review.
 
o  FUTURE BUDGET PERIODS - It is anticipated that direct cost budgets
will remain constant throughout the life of the project for all R01
applications (i.e., the same number of modules requested for all
budget periods).  All necessary costs should be considered when
determining the number of modules to be requested.  However, in the
exceptional event that the number of modules requested must change in
any future year, appropriate justification must be provided.  The
"Budget for Entire Proposed Project Period" (top section of Form Page
5) should include Total Direct Costs requested for each year and the
Total Direct Costs for the Entire Proposed Project Period.  The
Justification section should be completed based on instructions
provided on Form Page 5.
 
Because the FIRST (R29) Award applications may request different
direct costs not to exceed $100,000 in any given budget period and
are limited to a total direct cost cap of $350,000 for the entire
project period, the applicant should show the TOTAL DIRECT COST for
each of the five years listed on Form Page 5 of the 398 application
form.  These are the only cost elements required in the application.
 
o  SUBCONTRACTS - If collaborations or subcontracts are involved that
require transfer of funds from the grantee to other institutions, it
is necessary to establish formal subcontract agreements with each
collaborating institution.  A letter of intent from each
collaborating institution should be submitted with the application.
Initial and future year budgets for subcontracts should be prepared
using the same guidelines as for the main grant except that total
subcontract costs NEED NOT be in $25,000 modules.  Requested amounts
should be based on individual needs of the subcontract and should
reflect both direct and indirect costs.  When subcontract funds are
added to the main R01 grant budget, the total amount must conform
with the number of $25,000 modules requested.
 
o  BIOGRAPHICAL SKETCH - In addition to the standard information
requested on Form Page 6, the applicant has the option of providing
the title and source of any sponsored support relevant to the
proposed research.
 
o  OTHER SUPPORT - No other support information is required on "Other
Support" pages (Form Page 7).  Selected other support information
relevant to the proposed research may be included in the Biographical
Sketch as indicated above.  Complete other support information will
be requested by NHLBI staff if there is a possibility for an award.
 
o  CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by NHLBI staff
if there is a possibility for an award.
 
o  The applicant should provide the name and phone number of the
individual to contact concerning fiscal and administrative issues if
additional information is necessary following the initial review.
 
Submit a signed, typewritten original of the application and three
signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
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 Dr. C. James Scheirer, at the listed under LETTER OF
INTENT.
 
Applications must be received by June 11, 1996.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (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 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.
 
o  If  an application is determined to be unresponsive to the RFA,
the principal investigator will be notified and may request that the
application be returned or sent to DRG where it will be processed in
the next available cycle as a regular grant application.
 
o  A sample budget is available upon request from Mr. Raymond
Zimmerman at the number listed under INQUIRIES.
 
REVIEW CONSIDERATIONS
 
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 NIH peer
review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a review in
which only those applications deemed to have the highest scientific
merit of the applications under review (usually two to three times
the number of applications that the NHLBI anticipates being able to
fund under the program) will be discussed, assigned a priority score,
and receive a second level review by the National Heart, Lung, and
Blood Advisory Council.
 
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort and any changes requested in
future years.  The total budget request will be reviewed for
consistency with the proposed methods and specific aims.  The
duration of support will be reviewed to determine if it is
appropriate to ensure successful completion of the recommended scope
of the project.  The review criteria are the following:
 
o  scientific, technical or medical significance and originality of
proposed research
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research
 
o  availability of the resources necessary to perform the research
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA
 
The following will be considered in making funding decisions:
quality of the proposed project as determined by peer review,
availability of funds, and program priority.
 
The anticipated date of award is September 29, 1996.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct requests for the RFA to:
 
Monique Rush
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email: monique_rush@nih.gov
 
Direct inquiries regarding programmatic issues to:
 
Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email: hannah_peavy@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Raymond L. Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  raymond_zimmerman@nih.gov
 
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 a 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 the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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