SIMIAN MODELS FOR THE ORAL BIOLOGY OF HIV INFECTION AND AIDS-RELATED ORAL 
COMPLICATIONS 

RELEASE DATE:  February 24, 2004

PA NUMBER:  PAS-04-066

May 1, 2007  - This PA has been reissued as (PA-07-369).

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date. The 
non-AIDS portion of this funding opportunity expires on the date indicated below. 
A replacement R21 (PA-06-260) funding opportunity announcement has been issued 
for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:  
National Institute of Health (NIH)
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION: 
National Institute of Dental and Craniofacial Research (NIDCR) 
 (http://www.nidcr.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  
No. 93.121, Oral Diseases and Disorders Research

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PAS  

This Program Announcement with set-aside funds (PAS) solicits applications 
that will use nonhuman primate models to study the oral biology of HIV 
infection and the oral complications associated with AIDS.  This is an 
exploratory/developmental award with limited funding that is designed to 
maximize the use of animals currently involved in ongoing studies.  Studies 
that will increase our knowledge of the basic biology, pathogenic mechanisms, 
immunology, diagnosis, treatment, and prevention of oral HIV/AIDS in simian 
macaque models are requested.  Exploratory projects in emerging areas of 
importance for oral manifestations of AIDS and other acquired 
immunodeficiencies are of particular interest.  It is expected that 
investigators will base their studies on recent developments in the field and 
will make use of the new and emerging state of the art technologies.  

RESEARCH OBJECTIVES

Background:

Research on the oral biology of HIV infection and oral complications 
associated with immunosuppression in general, and AIDS in particular, has 
been hampered by the lack of reliable in vitro and in vivo models that 
recapitulate human infections.  Nonhuman primate models for AIDS however, 
have been shown to be useful in mother-to-infant transmission studies and 
evaluation of novel vaccine approaches as well as early immunologic events 
following simian immunodeficiency virus (SIV) and simian-human 
immunodeficiency virus (SHIV) infection.  SIV/SHIV can induce fatal 
immunosuppression in macaques, closely resembling AIDS in humans, but with a  
shorter incubation period and a more aggressive course (acute model).  
Certain variants and constructs of SHIV have been shown to induce simian AIDS 
after prolonged exposure (chronic model).  The virus progeny become 
neutralization resistant, acquire the ability to replicate in macrophages and 
maintain CXCR4 usage at later stages of disease.  The latter variants have 
the potential to induce a disease course with pathogenesis that approximates 
that induced by HIV in humans.  The acute and chronic models serve different 
purposes and are potentially invaluable for studying the oral biology of HIV 
infection, the oral complications associated with AIDS, and the interaction 
of innate and adaptive immune regulatory networks in virally-induced 
immunosuppression.  

The majority of HIV infections are initiated at mucosal sites.  This is 
followed by progressive loss of local and systemic immune responses, which 
eventually lead to opportunistic infections that primarily affect mucosal 
surfaces.  These occur despite the considerable innate and adaptive immune 
mechanisms of resistance expressed at and within mucosal surfaces exposed to 
infection.  Among the mucosal routes of transmission that HIV uses to infect 
the host is the oral mucosal tissue.  This route of infection has been shown 
in both humans and primates.  HIV RNA and proteins can be detected directly 
in the mucosa, as well as in the saliva from infected subjects.  However, 
infectious HIV virions are rarely found in the saliva, suggesting that the 
oral mucosa is not permissive for efficient HIV replication.  Our 
understanding of HIV pathogenesis is far from complete as is our 
understanding of how other opportunistic pathogens (HHV-8, CMV, EBV, HPV and 
Candida) infect and cause the oral complications associated with AIDS.  The 
ability of the oral cavity to resist HIV infection and replication while 
providing a safe haven for other pathogens provides a unique opportunity to 
dissect the differential patterns of host defenses.

Several of the complications associated with opportunistic infections 
occurring in HIV-infected individuals were reported to occur in non human 
primates.  For example, rhesus lymphocryptovirus, a simian homologue of human 
EBV, was shown to cause an simian AIDS-associated lymphoma that closely 
resembles pathologically and histologically that caused by EBV in AIDS-
associated non-Hodgkin’s lymphoma; retroperitoneal fibromatosis-associated 
herpesvirus (RFHV), a simian homolog of Kaposi's sarcoma-associated 
herpesvirus (KSHV), induces pathology in macaques that has similarities  to 
Kaposi's sarcoma; and, rhesus cytomegalovirus, the simian homolog of human 
CMV, infection, accelerates the state of immunosuppression induced by SIV in 
macaques and induces pathological changes in the immunocompromised animals 
similar to those induced by human CMV in AIDS patients.
                                                                                          
Scope:

Nonhuman primate animal models are especially useful as their biological 
systems and genetic composition closely resembles those of man.  The 
objective of this PAS is to encourage the solicitation of high risk/high 
impact exploratory/developmental studies that address HIV oral biology and 
AIDS-related oral complications in non human primate models for AIDS. 
Multidisciplinary collaborations are encouraged to achieve the desired goals. 
Examples of research responsive to this PAS are listed below but are by no 
means inclusive:

o   Characterize the oral complications of AIDS in macaques;
o   Determine the immunological, virological and biochemical basis of 
lesions induced by chronic viral infections of the oral cavity (e.g. 
papilloma virus, Kaposi sarcoma herpes virus, cytomegalovirus, etc.) in 
the context of SIV/SHIV infection;
o   Determine the structural, biological and functional properties of               
oropharyngeal mucosa that makes it resistant to HIV but susceptible to 
other viral pathogens; 
o   Compare the structural, biological and functional properties of oral 
mucosa from infants and adults to define the developmental impact on 
the susceptibility to HIV infection;
o   Determine the early events occurring in the oral mucosa and 
oropharyngeal lymphoid tissues following acute infection with SHIV and 
investigate whether the oral mucosa permits entry, transcytosis, 
harboring and shedding of SHIV;  
o   Characterize and compare the genetic and protein profiles of oral 
epithelial cells in healthy macaques and the SIV macaque-model of 
immunodeficiency;
o   Investigate and compare innate and adaptive immune networks of oral, 
vaginal, and rectal mucosal epithelial surfaces as they relate to 
SIV/SHIV infection; 
o   Identify and compare salivary components from infant and/or adult 
macaques that interact with SHIV and possibly control susceptibility of 
oral epithelium to SIV infection; 
o   Determine the impact of co-infections, inflammatory diseases, and 
tissue injury on mucosal susceptibility to SIV and development of AIDS; 
and, 
o   Apply genomic and/or proteomic approaches to determine gene expression 
in control and infected animals. 

Due to the limitations of the award, it is expected that the applicants will 
establish collaborations with investigators using the simian model for AIDS 
in ongoing studies. The applicants should submit evidence of the 
collaborative agreements to use the animals and perform the studies. 
Abstracts of currently NIH funded projects using macaque models are available 
from the CRISP Database: http://crisp.cit.nih.gov/ .  

MECHANISM OF SUPPORT 

Applicants responding to this PAS must use the NIH Exploratory/Developmental 
Research Grant (R21) award mechanism. The total project period for an 
application in response to this PAS may not exceed two years, with a combined 
budget for direct costs of up to $275,000 for the two year period. For 
example, the applicant may request $100,000 in the first year and $175,000 in 
the second year.  The request should be tailored to the needs of the project. 
Normally, no more than $200,000 may be requested in any single year. This R21 
cap may be exceeded by $25,000, direct costs per year to accommodate the 
facilities and administrative (indirect) costs associated with collaborative 
research at another institution. 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 NIDCR provide support for this program, awards pursuant to this 
PAS are contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications. The applicant will be solely 
responsible for planning, directing, and executing the proposed project. 

This PAS uses just-in-time concepts. It also uses the modular budgeting 
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).  All 
applications submitted in response to this announcement must use the modular 
budget format.  This program does not require cost sharing as defined in the 
current NIH Grants Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

Exploratory/developmental grant support is for new projects only; competing 
continuation applications will not be accepted.  Two revisions of a 
previously reviewed exploratory/developmental grant application may be 
submitted as defined in NIH Policy at 
http://grants.nih.gov/grants/policy/amendedapps.htm.

FUNDS AVAILABLE

NIDCR intends to commit approximately $800,000 each year in FY2004, FY2005 
and FY2006 to fund up to four grants per year in response to this PAS.  The 
usual PHS policies governing grants administration and management will apply. 
Although this program is provided for in the financial plans of the NIDCR, 
awards pursuant to this PAS are contingent upon the availability of funds for 
this purpose and the receipt of a sufficient number of applications of high 
scientific merit.  

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 institutions/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 underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PAS and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Isaac R. Rodriguez-Chavez, Ph.D., M.S., M.H.S. 
Director, AIDS and Immunosuppression Program
Division of Extramural Research, Integrative Biology and Infectious Diseases Branch, 
National Institute of Dental and Craniofacial Research 
6701 Democracy Blvd., Rm. 614 
Bethesda, MD 20892-4878 
Telephone: (301) 594-7985 
Fax: (301) 480-8319 
Email: isaac@nidcr.nih.gov

o Direct your questions about financial or grants management matters to:

Mary Daley
Grants Management Branch  
National Institute of Dental and Craniofacial Research
45 Center Drive MSC 6402
Building 45, Room 4AN-44B
Bethesda, MD  20892-6402
Phone: (301) 594-4808
Fax: (301) 480-3562
Email: md74u@nih.gov 

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements.  The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/.  The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact Grants Info, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of 
the application form and the YES box must be checked.

APPLICATION RECEIPT DATES:  Applications submitted in response to this PAS 
will be accepted at the standard AIDS application deadlines, which are 
available at http://grants.nih.gov/grants/dates.htm.  Application deadlines 
are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS: The page and appendix limits for R21 applications 
should be followed

1. RESEARCH PLAN:  Items a-d may not exceed fifteen (15) pages, 
including tables and figures.  The following information should be 
taken into account for items a, b and c:  

o   Item a, SPECIFIC AIMS--The instructions for this section suggest that 
the applicant state "the hypotheses to be tested".  Since some 
applications submitted in response to this RFA may also be design- or 
problem-driven (e.g., development of novel technologies), or need-
driven (initial research to develop a body of data upon which future 
research will build), hypothesis testing per se may not be the 
driving force in developing such a proposal and, therefore, may not 
be applicable.  The application should state the hypotheses, design, 
problem and/or need which will drive the proposed research.

o   Item b, BACKGROUND AND SIGNIFICANCE--In this section, it is       
important to identify clearly how the application addresses the      
specific objectives of this RFA and the purpose of the R21            
mechanism.

o   Item c, PRELIMINARY STUDIES/PROGRESS REPORT—No preliminary data are 
required for an R21 application.  

2.  APPENDIX.  Up to five articles may be submitted as appendix 
materials.  

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS:

Applications must be submitted in a modular budget grant format.  The modular 
budget 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.

SENDING AN APPLICATION TO THE NIH: Submit a signed, original of the 
application, including the checklist, and five 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)

APPLICATION PROCESSING: 

Applications must be mailed on or before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PAS 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 a substantial revision of an unfunded version of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks of submission.

PEER REVIEW PROCESS

Applications submitted for this PAS will be assigned on the basis of 
established PHS referral guidelines.   Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council 
or board.  

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate applications in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 
application:

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The 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, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 
forward.

SIGNIFICANCE: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced? What 
will be the effect of these studies on the concepts or methods that drive 
this field?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

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

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

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS 

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

AWARD CRITERIA

Funding decisions for this PAS will be based on: 

o   Scientific merit of the proposed project as determined by peer review
o   Availability of funds 
o   Relevance to program priorities
o   Evidence of collaborative agreements to use the animals and perform    
    the studies

REQUIRED FEDERAL CITATIONS 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

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 PAS 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 
PAS is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm. 

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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