ORAL TRANSMISSION OF HIV

Release Date:  September 20, 2001

RFA:  RFA-DE-02-001

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

Letter of Intent Receipt Date:  November 14, 2001
Application Receipt Date:       December 14, 2001

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN 
$250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN 
SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The overall goal of this initiative is to stimulate research on the oral 
transmission or inhibition of oral transmission of HIV.  Research applications 
are encouraged on: 1) prevention of postnatal transfer of HIV to infants via 
the oral route, 2) fundamental pathogenic mechanisms associated with oral 
transmission, 3) basic studies on how the virus enters the tissues, the first 
and subsequent cells infected, and role of co-infections and host factors in 
infection, 4) international studies that use a unique patient population for 
studies of oral transmission, and 5) inhibition of HIV oral transmission by 
oral components, and the development of potential HIV-inactivating/inhibiting 
substances.  Within these studies, research on the effects of gender, age, 
race and ethnicity on oral transmission is encouraged.  

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 Request for Applications (RFA), 
Oral Transmission of HIV, is related to the priority area, Oral Health.  
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

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.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) 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 four (4) 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.  The anticipated award date is June 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE 

The NIDCR intends to commit approximately $2 million in FY 2002 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 four (4) years and a budget 
for direct costs of up to $250,000 per year.  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 meritorious applications. 
At this time, it is not known if this RFA will be reissued.

RESEARCH OBJECTIVES

Background

The primary mode of human immunodeficiency virus (HIV) transmission worldwide 
is by exposure to the virus at mucosal surfaces.  In contrast to vaginal and 
rectal infection, transmission of HIV via the oral route has received 
relatively little study and the risks of oral infection are unclear.  HIV is 
introduced into the oral cavity of fetuses during in utero during development, 
infants during delivery and feeding on breast milk from infected mothers, and 
adults during the exchange of body fluids during heterosexual and homosexual 
oral-genital sexual activity.   

Epidemiological data have supported the premise that HIV transmission via 
saliva is low or non-existent.  Inhibitory factors in saliva include 
isotonicity, secretory IgA, salivary agglutinin proteins, and secretory 
leukocyte protease inhibitor.  However, oral infection with HIV in semen 
appears to be possible, although at a reduced level than that seen via 
rectal/vaginal intercourse.  Animal studies confirm that HIV can be 
transmitted via the oral tissues, and infect oral lymphoid cells, tonsils, as 
well as the salivary glands.  Oral trauma, co-infections with other sexually 
transmitted pathogens, periodontal diseases, concomitant ulcerative lesions, 
drug use, and smoking might further enhance oral HIV transmission.  

Oral tissues support HIV replication and may serve as a previously 
unrecognized HIV reservoir.  Local HIV production from oropharyngeal sites may 
be a key source of rebound virus that leads to virological failure in patients 
receiving highly active antiretroviral therapy (HAART.)  Most HIV+ patients 
have more virus in blood than saliva, possibly due to the potent HIV-
inhibitory properties of saliva.  However, some individuals are hyper-
excretors of HIV, carrying more HIV in saliva than in blood.  HAART therapy 
may not reduce HIV in saliva, for example, titers of HIV actually go up in 
semen of hyper-excretors when the patient is put on HAART.   With such high 
levels of infectious HIV in their saliva, hyper-excretors may be at risk of 
transmitting the virus to their partners even though the blood levels are low.  

Objective: 

The objective of this initiative is to reduce or prevent the risk of 
acquisition of HIV via oral transmission through the support of basic, 
epidemiological and clinical research.  Examples of research that might be 
responsive to this RFA include: 

O Studies on how to prevent postnatal transfer of HIV to infants via the oral 
route, 
O Determination of the pathogenic mechanisms associated with oral 
transmission, and a comparison with transmission via rectal/vaginal 
intercourse,  
O Studies on how the virus enters the tissues, the first and subsequent cells 
infected, the role of co-infections in infection, and studies of virus 
tropism, co-receptor usage, and cell-free versus cell-associated virus 
transmission,
O Studies that use a unique international patient population for studies of 
oral transmission, 
O Epidemiological investigations to evaluate the actual contribution of oral 
transmission of spread of HIV, 
O Studies on the modulating factors including conditions or practices that 
influence the integrity of the oral mucosa, oral health, nutrition, inhibitory 
substances in saliva, and the influence of alcohol, drugs, and other 
substances,     
O Determination of the influence of host factors and conditions, including 
gender, age, race and ethnicity, on oral transmission,
O Studies using non-human primates to study oral transmission, and,
O Delineation of the potential for prophylaxis before and after oral exposure 
to stop HIV infection.  

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 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 are provided indicating 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable, and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

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.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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.

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 plan the review.

The letter of intent is to be sent to Dr. George Hausch (see contact 
information below) by November 14, 2001.

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact the NIDCR Program staff members 
listed below with any questions regarding the responsiveness of their proposed 
project to the goals of this RFA or the preparation of their applications 
prior to submission of the application. 

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 5/2001 version.  
For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: 
GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 

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 NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  Applicants are permitted, however, 
to use the 4/1998 revision of the PHS 398 for scheduled application receipt 
dates until January 9, 2002.  If you are preparing an application using the 
4/1998 version, please refer to the step-by-step instructions for Modular 
Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm.  
Additional information about Modular Grants is also available on this site.

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.

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 to CSR, two additional copies of the application 
must be sent to:

H. George Hausch, Ph.D.
Scientific Review Branch
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44F
Bethesda, MD  20892-6402
Telephone: (301) 594-2904
FAX: (301) 480-8303
Email: George.Hausch@nih.gov

Applications must be received by December 14, 2001.  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 by CSR staff for completeness and 
responsiveness by the NIDCR.  If the application is not responsive to the RFA, 
CSR staff may contact the applicant to determine whether to return the 
application to the applicant or submit it for review in competition with 
unsolicited applications at the next review cycle.

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.  As part of the 
initial merit review, all applications will receive a written critique and 
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, assigned a priority score, and receive a second level 
review by the NIDCR 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 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 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:    November 14, 2001
Application Receipt Date:         December 14, 2001
Peer Review Date:                 March/April 2002
Council Review:                   May/June 2002
Earliest Anticipated Start Date:  June, 2002

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 answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dennis Mangan, Ph.D.
Infectious Diseases and Immunity Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-32F
Bethesda, MD  20892-6402
Telephone: (301) 594-2421
FAX: (301) 480-8318
Email: Dennis.Mangan@nih.gov

Direct inquiries regarding review issues to:

H. George Hausch, Ph.D.
Scientific Review Branch
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44F
Bethesda, MD  20892-6402
Telephone: (301) 594-2904
FAX: (301) 480-8303
Email: George.Hausch@nih.gov

Direct inquiries regarding fiscal matters to:

William Powell
Grants Management Branch
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44
Bethesda, MD  20892-6402
Telephone: (301) 594-4800
FAX: (301) 480-8301
Email: wp43y@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 Sections 301 and 405 of the Public Health Service Act as 
amended (42 USC 241 and 284) 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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