NONHUMAN PRIMATE MODELS OF HIV-ASSOCIATED PULMONARY, CARDIOVASCULAR, 
AND HEMATOLOGICAL DISORDERS 

RELEASE DATE:  December 4, 2002
 
RFA:  HL-03-005 

National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov)  

LETTER OF INTENT RECEIPT DATE: February 20, 2003

APPLICATION RECEIPT DATE: March 20, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA 

The National Heart, Lung, and Blood Institute (NHLBI) invites 
applications on the use of nonhuman primate models for the study of 
Human Immunodeficiency Virus (HIV)-associated pulmonary, 
cardiovascular, and hematologic disorders.  These primate models  
(e.g., Simian Immunodeficiency Virus [SIV]- and Simian-Human 
Immunodeficiency Virus [SHIV]-infected monkeys) should be designed to 
facilitate the study of the biological and clinical characteristics of 
disorders of lung, heart, blood, and bone marrow, associated with HIV 
infections and co-infections as well as to evaluate novel methods for 
prevention and treatment of these conditions.  

RESEARCH OBJECTIVES

Background  

HIV infection results in progressive damage of the immune system of 
infected individuals and makes them susceptible to a wide variety of 
opportunistic (bacterial, viral, fungal, and protozoan) infections.   
Lung infections that occur in patients during the course of HIV 
infection and AIDS (prominently among them, tuberculosis) represent a 
major cause of morbidity and mortality for HIV-infected individuals 
around the world.  Dual infection and synergism between HIV and 
Mycobacterium tuberculosis (Mtb) represent a worldwide health crisis 
affecting millions of people, especially in developing nations in 
Africa and Asia.  Each year an estimated 8 million people develop 
clinical tuberculosis and the annual death toll from this disease is 
estimated at 2 to 3 million people.  The majority of tuberculosis cases 
occur in the same populations in which there are also millions of cases 
of HIV infection.  Individuals infected with HIV are far more 
susceptible to Mtb infection than those without HIV infection.  
Therefore, dual HIV-Mtb infections in humans are extremely common and 
their clinical course is more severe and more rapidly fatal.  Likewise, 
infection with Mtb increases HIV production in patients with dual HIV-
Mtb infections and hastens the progression of AIDS and other HIV-
related diseases.  The concurrent presence of infections other than 
tuberculosis in the lungs of humans, such as Pneumocystis carinii 
pneumonia and pneumococcal pneumonia, can also increase the replication 
of HIV and accelerate the course of AIDS.  HIV-associated immune 
dysfunction increases the likelihood and severity of these lung 
infections and also appears to alter the pathogenesis and clinical 
course of these respiratory infections in ways that are different from 
other immunodeficient conditions.  By altering local immunity in the 
lung, HIV infection can also result in harmful inflammatory responses 
and infiltrates that may cause acute or chronic lung injury (e.g., HIV-
associated emphysema and pulmonary hypertension).

In the era prior to availability of highly active antiretroviral 
therapy, cardiac involvement in HIV disease was estimated to be 
approximately 6-7%.  Autopsy series and retrospective analyses suggest 
that cardiac lesions are present in 25-75% of patients with AIDS.  HIV-
related cardiovascular diseases include pericardial effusion, 
myocarditis, dilated cardiomyopathy, endocarditis, atherosclerosis, 
hypertension, malignant neoplasms and drug-related cardiotoxicity.  
Contributory roles of the HIV virus itself, the extent of 
immunodeficiency, and the existence of co-infection in the pathogenesis 
of HIV-associated cardiovascular disorders are not well defined. 
Furthermore, other factors such as inflammation, nutritional 
deficiencies, autoimmune responses, and pharmacologic effects of anti-
retroviral agents warrant exploration in the context of HIV-related 
cardiovascular disorders. SIV- and SHIV-infected non human primates 
provide an opportunity for in-depth, controlled study of these matters.

Blood- and marrow-related disorders have been observed in SIV-infected 
monkeys, and parallel findings have been found in humans infected with 
HIV.  Therefore, the nonhuman primate model system is useful for 
furthering our understanding of the mechanism(s) associated with these 
disorders and for exploring strategies for prevention and treatment.
Hematopoietic abnormalities associated with HIV infection include: 
decreased proliferation of hematopoietic stem and progenitor cells, 
increased destruction of mature cells, and alterations in the 
supportive marrow stromal environment and in the production of 
regulatory cytokines.  The pathophysiologic mechanisms of these 
abnormalities are poorly understood and require study.  Also, it is 
known that thrombocytopenia is one of the earliest manifestations of 
HIV infection in human and primates.  HIV infection of humans is likely 
to bring about changes in the functions of cytokines and matrix 
proteins, in the migration of megakaryocytes, and in the production and 
destruction of platelets (which can lead to development of 
thrombocytopenia).  

Many opportunistic infections involve pathogenic agents that encode and 
express proteins that, in turn, modulate host immune responses.  The 
synergism of these molecules during co-infection may profoundly alter 
lymphoid cell trafficking, signaling, and function.  These effects may 
have profound implications on homeostatic regulation of the heart, 
lung, and bone marrow.  The roles that dendritic cells play in the 
initial systemic infection by virus, in the induction of humoral and 
cell-mediated immunities, and in the development of local immunity need 
to be actively investigated.    

Objective and Scope

Since the discovery of the SIV in 1984, the disease that occurs in 
experimentally infected nonhuman primates (i.e., simian AIDS) has been 
extensively investigated and is considered a useful model for the study 
of human AIDS.  This model has been utilized to assess HIV 
pathogenesis, to validate therapies, and to develop and test AIDS 
vaccines.

Through this initiative, we wish to stimulate collaborations among 
scientists devoted to studies of SIV/SHIV disease in primates as a 
model for human AIDS, and investigators with expertise and experience 
in the following fields of relevant research: studies of tuberculosis, 
Pneumocysis carinii pneumonia, pneumococcal pneumonia, and other 
pulmonary and cardiovascular infections/disorders and studies of the 
roles of blood cellular components in the genesis and progression of 
AIDS.  Such collaborations should take advantage of the large wealth of 
knowledge and resources (e.g., biological and immunologic reagents) 
that have been generated during the past 15 years.
  
Some examples of research topics that will be considered responsive to 
this RFA include, but are not limited to:

o Analysis of local immunological status, and heart or lung pathology, 
in the course of acute and chronic SIV/SHIV infection and simian AIDS

o Research to elucidate the mechanism(s) of cardiac ventricular 
dysfunction associated with HIV infection

o The study of SIV/SHIV-Mtb co-infections aimed at the understanding of 
their molecular and biological interactions and their synergistic 
effect(s) on the lung immune system

o Research to determine the mechanism by which Tumor Necrosis Factor-
alpha (TNF-alpha) inhibitors, used for the management of diseases like 
rheumatoid arthritis and Crohn's disease, can re-activate latent Mtb 
infection and promote the development of extrapulmonary tuberculosis

o Analysis of the status of the different bone marrow components during 
the course of SIV/SHIV infection and progression to simian AIDS  

MECHANISM OF SUPPORT
 
This RFA will use the R01 (investigator-initiated research project 
grant) award mechanism.  As an applicant, you will be solely 
responsible for planning, directing, and executing the proposed 
project.  This RFA is a one-time solicitation.  Future unsolicited, 
competing-continuation applications based on this project will compete 
with all investigator-initiated applications and will be reviewed 
according to the customary peer review procedures.  The anticipated 
award date is September 30, 2003.  

This RFA uses just-in-time concepts (e.g., for documentation of 
appropriate animal welfare requirements).  It also uses the modular as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise, 
follow the instructions for non-modular research grant applications.

Since the total costs for a subcontract or consortium are included in 
the direct cost request, one additional module of $25,000 above the cap 
may be requested for the facilities and administrative costs associated 
with third party agreements A module requested for this purpose must be 
clearly identified in the budget justification section of the 
application, and will be restricted for this purpose only at the time 
of award.

FUNDS AVAILABLE  

The NHLBI intends to commit approximately $3.8M in FY 2003 to fund five 
to seven new and/or competitive continuation grants in response to this 
RFA.  An applicant may request a project period of up to 5 years and a 
budget for direct costs of up to $500,000 per year.  We recognize that 
a dramatic shortage of primates available for research exists at 
present in this country; because of this, collaborations with 
institutions outside of the United States may be considered.  Because 
the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and 
duration of each award will also vary.  Although the financial plans of 
the NHLBI provide support for this program, awards pursuant to this RFA 
are contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications.

Although interested in this area of research, the National Institute of 
Allergy and Infectious Diseases (NIAID) is not participating in this 
initiative.

ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based or community-based organizations 
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
under-represented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS 

Inclusions

o Optimal utilization of the resources generated under this RFA is 
strongly recommended; therefore, a plan for proper acquisition and 
storage of non human primate tissue, to be made available to interested 
and qualified investigators for further study, is required as part of 
the application.   Investigators should include a request for funds in 
the budget for this purpose.
  
o Furthermore, investigators should indicate their willingness to 
participate in a meeting to determine how to standardize tissue 
collection and storage and to develop criteria for fair distribution of 
the samples; funds should be set-aside for this purpose.
  
o The applicants should also state their willingness to provide 
detailed descriptions of protocols and phenotypes.
  
o To be responsive to this announcement, applications must propose 
collaborations between scientists devoted to studies of SIV/SHIV 
disease in primates, as a model for human AIDS, and investigators who 
are documented experts in lung, cardiovascular, or blood diseases.

Exclusions

o Applications that lack a statement of willingness to share tissues and 
data with other investigators. 

o The establishment of new primate facilities will not be supported by 
this RFA.

Grantees' Meetings

Upon initiation of the program, the NHLBI will sponsor annual meetings 
to encourage exchange of information and dissemination of results among 
investigators who participate in this program.  In their budgets, 
applicants should include funds for annual one-day grantees' meetings, 
to be held, most likely, in Bethesda, Maryland.  Applicants should also 
include a statement in their applications that indicates their 
willingness to participate in these meetings.  

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and we welcome the 
opportunity to answer questions from potential applicants.  Inquiries 
may fall into three areas: scientific/research, peer review, and 
financial or grants management issues.

Please direct your questions about scientific/research issues to:

Sandra Colombini Hatch, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301) 435-0222
FAX:  (301)-480 3557
Email:[email protected]

Luiz Barbosa Ph.D.
Division of Blood Disease Research
National Heart Lung and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD  20892-7950
Telephone:  (301) 435-0075
Fax: (301) 480-0868
Email: [email protected]

Diane Reid M.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7940
Bethesda, MD  20982-7940
Telephone:  (301) 435-0515
Fax: (301) 480-1336
Email:  [email protected]

Please direct your questions about peer review issues to:

Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute 
6701 Rockledge Drive 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone: (301)435-0270 
FAX:  (301)480-0730
Email: [email protected]

Please direct your questions about financial or grants management 
matters to:

Robert A. Pike
Division of Extramural Affairs
Grant Operation Branch
National Heart, Lung, and Blood Institute 
6701 Rockledge Drive 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone:  (301) 480-0182
FAX: (301) 4803310
Email: [email protected]
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research;
o Name, address, telephone number, and e-mail address of the Principal 
Investigator;
o Names of other key personnel;
o Participating institutions; and
o Number and title of this RFA 

Although a letter of intent is not a requirement, is not binding, and 
does not enter into the review of a subsequent application, the 
information that it contains allows IC staff members to estimate the 
potential review workload and to plan the review.  Letters of intent 
should be sent by the date listed at the beginning of this document to 
Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES.

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, E-mail: [email protected].
 
SUPPLEMENTAL INSTRUCTIONS: 

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: 
Applications requesting up to $250,000 per year in direct costs must be 
submitted in a modular grant format.  The modular grant format 
simplifies the preparation of the budget in these applications by 
limiting the level of budgetary detail.  Applicants request direct 
costs in $25,000 modules.  Section C of the research grant application 
instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

Applications requesting up to $250,000 per year in direct costs must be 
submitted in a modular grant format.  Applications requesting one 
module ($25,000) above the cap due to subcontract or consortium 
facilities and administrative costs associated with third party 
agreements must also be submitted in modular format and may request up 
to $275,000 per year in direct costs.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  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. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package 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)
 
At the time of submission, two additional copies of the application and 
all five collated sets of appendix material must be sent to Dr. Anne 
Clark at the address listed under WHERE TO SEND INQUIRIES.

Please note that applications delivered by individuals are no longer 
accepted; all applications must either come via courier delivery or the 
United States Postal Service 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).

APPLICATION PROCESSING: Applications must be received by the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review.
 
The Center for Scientific Review (CSR) 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 CSR 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.

Principal investigators should not send supplementary material without 
first contacting the Scientific Review Administrator (SRA).  The SRA 
will be identified in the letter sent to you indicating that your 
application has been received.  If you have not received such a letter 
within three weeks after submitting the application, contact Dr. Anne 
Clark at the address listed under WHERE TO SEND INQUIRIES.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the (IC).  Incomplete and/or non-responsive 
applications 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 (IC) in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a second level review by the NHLBI National Advisory Council. 
 
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments, reviewers will be asked to discuss the 
following aspects of your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your application does not need to 
be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, 
you 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 your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for animals, or 
the environment, to the extent they may be adversely affected by the 
project proposed in the application.

o DATA SHARING:  The adequacy of the proposed plan to share tissue and 
data. 

o The capacity to show an optimal utilization of the resources (e.a. a 
plan to utilize the same experimental animals and controls to answer 
multiple biological questions and a plan for storage of tissue as 
indicated in the Special Requirement section of this RFA).

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: Feb 20 2003
Application Receipt Date: March 20 2003
Peer Review Date: June/July 2003
Council Review: September 4-5, 2003
Earliest Anticipated Start Date: September 30, 2003

AWARD CRITERIA 

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.
 
AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.838 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies described 
at http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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