HIV/AIDS ASSOCIATED ORAL VIRAL INFECTIONS

Release Date:  February 7, 2000

RFA:  DE-00-002

National Institute of Dental and Craniofacial Research 
http://www.nidcr.nih.gov/ 

Letter of Intent Receipt Date: May 15, 2000
Application Receipt Date: August 18, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" 
CONCEPTS.  IT INCLUDES DETAILED MODIFICATIONS TO STANDARD 
APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING 
APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute of Dental and Craniofacial Research (NIDCR) invites 
new and experienced scientists to submit research grant applications for 
basic, behavioral, epidemiological or clinical investigations to study the 
pathogenesis, infectivity, transmission, reactivation and pathotropic spread 
of viral infections in the oral cavity of the immunocompromised host.  This 
RFA is intended to solicit a broad range of research proposals on oral 
opportunistic infections with viruses, including human herpesvirus (HHV), 
Epstein Barr virus (EBV), cytomegalovirus (CMV) varicella-zoster virus (VZV), 
and human papillomavirus (HPV) in HIV-infected/AIDS individuals.  The 
Institute encourages collaborative projects that bring together investigators 
from all relevant scientific disciplines including microbiology, immunology, 
biochemistry, and pathology interested in studying viral infections of the 
oral cavity.  Applications that include collaboration with foreign scientists 
conducting unique research on this topic are also encouraged. 

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/AIDS Associated Oral Viral Infections, is related to 
the priority area of Oral Health.  Potential applicants may obtain a copy of 
"Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.

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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.  Although an application must be submitted from a single 
institution, collaborative arrangements with other institutions are 
encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed 5 years.  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.  New investigators without prior R29 or R01 support are strongly 
encouraged to apply.  They should identify their status on the cover page for 
the application.  The anticipated award date is February 1, 2001.

FUNDS AVAILABLE

The NIDCR intends to commit approximately $2 million in FY 2001 to fund 6 or 
7 new and/or competing 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 $200,000 per year.  Applicants with collaborative 
agreements at other domestic universities can apply for direct costs of up to 
$225,000, since facilities and administrative (F&A) costs on the consortium 
are included in the direct costs of the applicant.  Because the nature and 
scope of the research proposed may vary, it is anticipated that the size of 
each award will also vary.  Although the financial plans of the NIDCR 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 applications 
of outstanding scientific and technical merit. 

RESEARCH OBJECTIVES

Background

Oral viral infections and lesions may develop during the acute phase of HIV-1 
infection, early in the transition from HIV-1 infection to full blown AIDS, 
and if untreated, these infections and ulcerations may persist throughout the 
disease and add to the morbidity and mortality of the illness.  As the number 
of CD4+ T lymphocytes decline, the HIV-1 infected person becomes increasingly 
susceptible to infection with a wide variety of opportunistic oral pathogens 
including viruses and Candida species.  Highly active anti-retroviral therapy 
(HAART) has dramatically reduced the oral complications of AIDS, including 
viral infections, for patients who adhere to the regimen.  Patients who fail 
or do not have access to HAART treatments, patients during the acute phase of 
the HIV-1 infection and those transiting from HIV-1 infection to full blown 
AIDS are still at great risk of developing oral opportunistic infections.  
The NIDCR has recently requested submission of applications for research on 
the host immune response to Candida albicans [see NIH Guide to Grants and 
Contracts, December 17, 1999; 
http://grants.nih.gov/grants/guide/1999/99.12.17/index.html].  The present 
RFA encourages the submission of applications to study the viruses that cause 
oral complications associated with HIV infection/AIDS.  These viruses include 
herpesviruses (EBV, HSV-1, 2, 6 and 8, CMV, VZV), and papillomaviruses (HPV- 
6, 11, 13 and 30). 

Among the most severe, persistent, frequent, and recurrent infections in the 
oral cavity of the HIV-infected patient are those caused by herpesviruses.  
Four of the eight identified herpesviruses that cause human disease are 
responsible for oral ulcerations: HSV-1, HSV-2, VZV and CMV.  These ulcers 
are particularly aggressive and are slow to heal in the immunocompromised 
individual.  There is a greater tendency for oral infections to become 
systemic in HIV positive patients than in immunocompetent individuals.  The 
symptoms of herpetic lesions include fever, malaise, cervical 
lymphadenopathy, multiple oral ulcerations and intensely painful gingival 
erythema.  In those who are severely immunocompromised, infections can be 
caused by the reactivation of latent HSV infection in the oral tissues.  The 
oral lesions of most HSV infections are most commonly found on the hard 
palate, gingival keratinized epithelium or alveolar ridges.  The incidence of 
VZV infections increases with age and immunosuppression in HIV positive 
individuals (<200 CD4+ cells/mm3).  VZV causes severe, life threatening 
infections in immunocompromised patients. The first manifestation of the 
disease is vesicles that rupture and form ulcers.  Lesions appear as multiple 
small shallow ulcers on an erythematous base, usually on the palate.  
Cytomegalovirus is the most common opportunistic viral pathogen among people 
with AIDS.  In the oral cavity it causes ulcers that usually appear as single 
ulcers without the initial formation of vesicles.  Almost all homosexual 
males who are HIV positive show evidence of previous exposure to CMV.  In 
1996, CMV caused 53% of the oral ulcers found in HIV infected people.  
Approximately one quarter of HIV infected individuals are co-infected with 
both CMV and HSV, making diagnosis difficult and complicating the course of 
disease.  Individuals who are severely immunocompromised (<100 CD4+ cell/mm3) 
frequently have intraoral CMV ulcers, and these lesions may be the first sign 
of disseminated HIV infection. CMV has increased pathogenicity in 
immunosuppressed individuals and along with other Herpes viruses has 
immunosuppressive qualities.

Among the other herpesviruses involved in oral lesions, HHV-8 has been 
implicated as the etiological agent of Kaposi’s sarcoma (KS), which is the 
most common intraoral malignancy seen in HIV infected individuals.  Almost 
90% of severely immunosuppressed HIV positive patients (<100 CD4+ cells/ mm3) 
develop oral KS.  The herpesvirus, EBV, is considered to be one of the 
etiological agents responsible for oral hairy leukoplakia (OHL).  OHL 
develops as a white shaggy patch on the lateral surface of the tongue, and 
may extend to the dorsal and ventral surfaces. Candida albicans infections 
may be superimposed on the OHL lesion, making it a painful lesion not easy to 
diagnose or treat.  EBV infection has also been implicated in the development 
of lymphomas in the oral cavity.

HPV is a cause of a multiform group of oral hyperplastic nodular or papular 
lesions, including oral papillomas, verruca vulgaris (warts), focal 
epithelial hyperplasia, and condyloma acumininatum, a sexually transmitted 
disease with manifestations as oral warts.  An increased frequency of skin, 
anal and oral lesions or nodules due to HPV has been noted in HIV 
immunosuppressed children and adults.  Although HAART therapy has somewhat 
contained the growth of certain opportunistic pathogens, HPV infections may 
in fact have increased in the oral cavity.  

Viral infections in HIV-infected individuals are often painful, esthetically 
displeasing, and impair the normal function of the mouth.  Current medical 
practice does not have the means to adequately detect, diagnose and treat 
these oral viral lesions, nor can infection or reactivation be predicted or 
prevented.  To improve health care for HIV-infected patients specifically, 
and immunosuppressed individuals in general, more research on oral virus 
diseases and conditions is clearly needed.  Such research is expected to 
provide important information toward understanding the pathogenesis and 
treatment of oral viral infections in patients with immune compromise.

Research Objectives and Scope

The goal of this RFA is to increase our understanding of how virulence, 
infection, and host response is modified in the immune compromised patient to 
allow infection, activation or reactivation of opportunistic pathogens. This 
understanding can lead to improved diagnosis, prevention and treatment 
strategies, for the various opportunistic pathogens.

Investigators are not limited to the examples given and are encouraged to 
propose other projects that are appropriate to the investigator-initiated 
grant mechanism and to the study of opportunistic viral infections of the 
oral cavity.  Viruses other than those mentioned above might be appropriate 
for this RFA provided they specifically infect or cause oral lesions in the 
HIV-infected/AIDS individual.  Areas of research interest include work to:
o   Elucidate the role of the immune response in control or exacerbation 
of oral viral infections and lesions.
o  Explore viral cellular transformation and induced oncogenesis in the 
oral cavity of HIV-infected patients.
o  Identify modes of passive and adaptive immune modulation to control 
oral viral infections.
o  Characterize the host genetic susceptibility to viral oral infections. 
o  Elucidate the initiation and progress of viral pathogenesis in the oral 
cavity.
o  Explore the mechanisms of interactions between two or more viruses that 
may lead to different pathogenic outcomes. 
o  Identify the mechanisms of reactivation of viral infections in the oral 
cavity. 
o  Develop diagnostics for the early detection of sentinel lesions.

SPECIAL REQUIREMENTS

Awardees will be requested to attend a meeting to present the progress of the 
work funded under this program.  Details of this meeting will be provided 
post-award.  Applicants should include travel funds in their budgets for a 
two-day meeting every year, most likely to be held in Bethesda, Maryland, to 
meet with other NIDCR-supported researchers studying the oral complications 
of HIV infection and AIDS. Applicants should also include a statement in 
their applications indicating their willingness to participate in these 
meetings.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women, members of minority groups and their 
sub-populations 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 policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research", published in the Federal Register of March 28, 1994 (FR 59 14508-
14513), and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 
18, 1994, available on the web at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.  All investigators proposing research 
involving human subjects should read the "NIH Policy and Guidelines" on the 
Inclusion of Children as Participants in Research Involving Human Subjects 
that was published in the NIH Guide for Grants and Contracts, March 6, 1998, 
and is available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.  
Investigators also may obtain copies of these policies 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 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 
a subsequent application, the information that it contains allows NIDCR staff 
to estimate the potential review workload and avoid conflicts of interest in 
the review process.

The letter of intent receipt date is listed in the heading of this RFA and 
should be sent to the program staff listed under INQUIRIES.

APPLICATION PROCEDURES

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application form, PHS 398 (revised 4/98) is to be 
used in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $200,000 per year ($225,000 for applicants 
with consortium arrangements with other domestic universities.)  The modular 
budget request must be in accordance with the modifications made to the 
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $200,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative  (F&A) costs] for the initial 
budget period Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398. It is not required and will not be accepted with the 
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not required 
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project. Indicate whether the collaborating institution 
is foreign or domestic. The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include a Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for 
all key personnel, following the instructions below. No more than three pages 
may be used for each person. A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

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. 

The RFA label available in the PHS 398 (rev. 4/98) 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 (DE-00-002) must be typed on line 2 of the face page of the 
application form and the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three (3) signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH 
SUITE 1040
6701 ROCKLEDGE DRIVE, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)


At the time of submission, two (2) additional copies of the application must 
be sent to:

Dr. H. George Hausch
Scientific Review Branch 
Division of Extramural Research
National Institute for Dental and Craniofacial Research 
45 Center Drive, Room 4AN-38D- MSC 6402
Bethesda, MD 20892-6402

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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness and 
responsiveness by the CSR and NIDCR.  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 NIDCR in accordance with the review criteria stated below.  A 
process will be used by the initial review group in which all applications 
receive a written critique but only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed, assigned a priority score, and receive a second 
level review by the National Advisory Dental and Craniofacial Research 
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 the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals. Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application. Note that 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.

(1) 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?

(2) 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?

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

(4) 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)?

(5) 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups and children, as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of study subjects will also 
be evaluated.

o The reasonableness of the proposed budget and duration in relation to the 
proposed research

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

SCHEDULE: 

Letter of Intent Receipt Date:  May 15, 2000
Application Receipt Date:       August 18, 2000
Peer Review Date:               September, 2000
Council Review:                 January, 2001
Anticipated Start Date:         February 1, 2001

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.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Denise Anne Russo, Ph.D. 
Infectious Diseases and Immunity Branch
Division of Extramural Research,
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18B 
Bethesda, MD 20892-6402
Telephone: (301) 594-2617 
FAX: (301) 480-8318
Email: Denise.Russo@nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Kevin Crist
Grants Management Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44A, MSC 6402
Bethesda, MD 20892-6402
Telephone: (301) 594-4800
FAX: (301) 480-8301
Email: Kevin.Crist@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.121, Oral Diseases and Disorders Research Awards.  Awards are made under 
authorization of the Public Health Service Act, Title IV, Part A (Public Law 
78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant 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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