ROLE OF THE ORAL ENVIRONMENT IN HIV TRANSMISSION AND PATHOGENESIS

NIH Guide, Volume 26, Number 38, November 21, 1997

RFA:  DE-98-007

P.T.

National Institute of Dental Research
National Institute of Mental Health

Letter of Intent Receipt Date:  February 1, 1998
Application Receipt Date:  March 12, 1998

PURPOSE

The National Institute of Dental Research (NIDR) and the National Institute of
Mental Health (NIMH) invite applications to support outstanding multidisciplinary
research to: (1) determine whether or not HIV can be transmitted through the oral
cavity; (2) elucidate the mechanisms of possible HIV and HIV-associated disease
transmission through the oral cavity; and (3) identify socio-behavioral risk(s)
associated with patterns and/or characteristics of oral-genital contact and
design approaches to increase protective behaviors reducing risks of HIV
transmission via the oral route.  The Institutes are interested in supporting
multidisciplinary research in these areas conducted by scientists from the fields
of virology, immunology, genetics, oral biology, biochemistry, social and
behavioral sciences, and epidemiology.

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 RFA, Role of the Oral Environment in
HIV Transmission and Pathogenesis, is related to the priority area of HIV
infection.  Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report: Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Office, Washington, DC
20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, including universities, colleges, hospitals,
laboratories, units of State and local governments and eligible agencies of the
Federal government.  Applications from investigators representing racial/ethnic
minorities as well as from women and persons with disabilities. Although an
application must be submitted from a single institution, collaborative
arrangements with other institutions are strongly encouraged.  Also, applications
are not restricted to traditional dental, oral and craniofacial research
settings.

MECHANISM OF SUPPORT

The mechanisms of support utilized will be the individual research project grant
(R01).  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 five years.  This
RFA is a one-time solicitation for new and competing renewal awards.  Future
competitive renewal applications will compete with all investigator-initiated
applications and will be reviewed according to customary referral and review
procedures.  New investigators without prior R29 or R01 support are strongly
encouraged to apply.  They should identify their status in a cover letter as well
as in the application and provide evidence of institutional support for the
research.

FUNDS AVAILABLE

The estimated total costs (direct plus indirect) available for the first year of
support for awards under this RFA will be $3 million.  The NIDR plans to support
or contribute to the support of a total of approximately 12 grants in response
to this RFA in fiscal year 1998. NIMH will allocate $750,000 in direct costs for
FY 98 to support 2 to 3 individual R01s, provided the applications are of high
scientific merit. It is possible that in a topic area that overlapped the
interests of NIMH and NIDR could be co-funded by these two Institutes if the
project was of high scientific merit.  Grant awards will be contingent on the
receipt of high quality applications and the availability of funds.  Applications
may not request more than three percent annual increases for inflation over
subsequent years.  Usual PHS policies governing grants administration and
management will apply.  Funding beyond the first and subsequent years of the
grant will be contingent upon satisfactory progress during the preceding years
and the availability of funds.

RESEARCH OBJECTIVES

Background

According to the World Health Organization, 22 million men, women and children
are infected with HIV-1 worldwide, and the number of infected people is expected
to exceed 40 million by the year 2000.  It is estimated that 8,500 new HIV
infections occur every day.  In the United States, the demographics are changing
with increased heterosexual transmission to women and a disproportionate increase
in incidence of infection in racial and ethnic minorities.  The death rate from
AIDS for black men is four times that for white men and for black women it is
nine times that for white women. This astonishing worldwide growth of the HIV
pandemic is matched by an explosion of information in the areas of HIV virology,
transmission, pathogenesis, prophylaxis and development of impressive treatment
options for HIV and HIV-associated opportunistic infections. However, it is clear
that the epidemic will continue to grow and extend particularly among ethnic
minorities, the poor, the medically underserved, women and children in the United
States and dramatically in much of the developing world, especially since the new
HIV therapies are not economically feasible for many developing countries and not
all people can manage the complicated treatment regimen.

HIV infection is predominantly sexually transmitted.  Although one-half of the
reported cases of AIDS in the United States are still among homosexual men,
heterosexual transmission is clearly the most common mode of infection worldwide,
particularly in developing countries.  It has become clear that the virus can be
transmitted to either partner through vaginal or anal intercourse.  Oral sex
appears to be a much less efficient mode of transmission of HIV. In this regard
there is a perception, particularly among some subgroups, that oral sex is a form
of 'safe sex'.  This presents a concern, as there have been reports of documented
HIV transmission resulting solely from receptive fellatio and insertive
cunnilingus. For example, one study reported that in 12 subjects where the
precise date of seroconversion could be identified, 4 individuals reported oral-
genital contact as their sole risk factor.  In another study it has been shown
that SIV infection can be transmitted by deposition of virus in the oral cavity. 
However, there is no convincing evidence that saliva is the vehicle by which  HIV
infection is accomplished through exposures of the oral cavity.

Postnatal oral transmission of HIV to infants has been clearly documented,
strongly implicating colostrum and breast milk as the vehicles of infection.
However, the mechanisms of postnatal HIV infection during breast feeding are
unclear.  In breast-fed infants, where the upper intestinal mucosa is involved,
it is critical to establish the mechanism by which  HIV is transmitted from the
mother to the neonatal host; for example, identification of the compartments
harboring the virus, elucidation of the portal of HIV transmission, and
identification of  potential innate maternal and neonatal antiviral molecules
(i.e., antibodies, chemokines, SLPI) which may account for protection in the
infants who do not get infected and may provide important insights for augmenting
defense against HIV infection.

Rationale

In order to identify current and future research opportunities in the areas of
AIDS research relevant to the mission of the Institute,  an ad hoc panel was
convened on April 24-25, 1997 by the NIDR.  The panel members were from academia,
industry, the National Advisory Dental Research Council, and other  NIH
Institutes and Federal agencies. It was  agreed that the NIDR is uniquely
positioned to pursue three important areas of AIDS research, namely those
involving oral transmission of HIV, opportunistic infections of the oral cavity,
and mucosal immunity and the development of vaccines. Within the area of oral
transmission,  the following research initiatives were recommended: i)
epidemiology to evaluate the possible contribution(s) of oral transmission of
HIV; ii) the etiology and pathogenesis of virus entry after oral exposure,
predisposing factors, immune dysfunction, assessment of oral viral load, virus
tropism and iii) socio-behavioral factors in order to document types of sexual
activity related to oral-genital contact and the design of effective approaches
to reduce this pathway of risks of HIV infection.

Proposed Research

The following research topics are appropriate for this RFA.  They are provided
as examples and are not intended to be inclusive or restrictive.

o  Explore the mechanisms of virus entry after oral exposure.  Key issues to be
addressed are: i) elucidation of the site(s) of viral entry after oral exposure
across mucosal surfaces of the oropharyngeal and gastrointestinal tract; ii)
identification of the initial target cells and their receptors, initial site(s)
of replication and the relative efficiency of oral infection compared to other
routes of exposure.

o  Develop new or use existing animal models to study viral entry and to follow
the progression of virus from the initial interaction to the establishment of HIV
pathogenesis. The SIV model can be exploited but also new opportunities for other
primate models and viral strains as well as the creation of transgenic animals
should be explored.

o  Conduct studies to compare bronchial, vaginal, rectal and oral mucosal sites
to characterize unique and common immunological parameters relevant to HIV
infection. Explore the presence of chemokine receptors and their ligands in these
sites, and examine the mechanisms by which M cells and dendritic cells contribute
to the internalization of the virus and to the viral selection process.

o  Delineate aspects of tonsils and their function contributing to initial HIV
infection, their status as viral reservoirs, induction of virus production and
as therapeutic targets.

o  Explore the role of cytokines on the dysregulation of IgA production and
transport; characterize the properties of salivary IgA antibodies in HIV infected
people, and the role alterations in salivary cytokines have on those events, as
well as the potential for intracellular formation of IgA anti-HIV/HIV complexes.
Design epidemiological investigations to examine the relative risk of oral
transmission of HIV and identify factors [e. g., oral lesions, sexually
transmitted diseases (STDs), social mixing and level of seroprevalence, different
types of substance abuse] which increase risks of transmission during oral sex.

o  Conduct studies to examine socio-behavioral factors (e.g., patterns and/or
characteristics of oral-genital sexual behavior) related to oral transmission;
design effective behavioral approaches including protective strategies to reduce
the risk of possible HIV transmission through the oral cavity.

o  Assess the effectiveness  and acceptability of protective strategies for
eliminating or reducing risks of oral HIV transmission among population
subgroups; identify effective strategies for disseminating information on risks
and protective behaviors to health professionals and high risk population
subgroups.

o  Develop more sensitive and specific oral HIV diagnostic tests; delineate the
mechanisms of action of antiviral molecules in saliva including mucosal peptides
(i.e., defensins, magainins), secretory leukocyte protease inhibitor (SLPI) and
thrombospondin-1; design therapeutic strategies based on these molecules to block
HIV-1 infection; develop novel drug delivery systems that would target the oral-
nasal-pharyngeal region.

o  Identify compartments harboring HIV in breast milk; elucidate the portal of
HIV transmission in breast feeding; identify potential innate maternal and
neonatal antiviral molecules (i.e., antibodies, chemokines, SLPI) which may
account for protection in the infants who do not get infected, and may provide
important insight into mechanisms to augment defense against HIV infection.

o  Examine the role of opportunistic pathogens (e.g. Candida, HHV8, EBV, HPV) in
facilitating HIV transmission/infection, pathogenesis and associated oral
manifestations.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
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," which have been 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 1, 1998 a letter of
intent that includes a descriptive title of the proposed research,  the name,
mailing address, FAX, email address, and telephone number of the Principal
Investigator and the identities of other key personnel and participating
institutions and departments, 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 is
helpful in planning for the timely review of the applications. It helps NIDR
staff to estimate the potential review workload and to avoid possible conflicts
of interest in the review.  The letter of intent is to be addressed to Dr. Eleni
Kousvelari at the address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:
ASKNIH@od.nih.gov.  The forms are also available on the NIH World Wide Web Home
Page at http://grants.nih.gov/grants/funding/phs398/phs398.html.

The RFA label available in the PHS 398 application form kit must be affixed to
the bottom of the face page of the original and the original must be placed on
top of the entire package. 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, in order to identify the application as a response
to this RFA, the RFA title ("Role of Oral Environment in HIV Transmission and
Pathogenesis") and number, DE-98-007 must be typed in item 2 of the face page of
the application form and the YES box must be checked.  The instructions
accompanying Form PHS 398 must be followed as far as possible.

Applicants from institutions that have a General Clinical Research Centers (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
Center as a resource for conducting the proposed research.  If so, a letter of
agreement from the GCRC Program Director must be included in the application
material.

Submit a signed, typewritten original of the application, including a cover
letter, the checklist and three signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must also be
sent to:

Dr. H. George Hausch
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-38D
Bethesda, MD  20892-6402

Applications must be received by March 12, 1998.  If an application is received
after that date, it will be returned to the applicant without review.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be assigned on the basis of established PHS referral
guidelines. Upon receipt, applications will be reviewed for completeness by the
Center for Scientific Review (CSR), NIH.  Incomplete 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 a special emphasis panel convened by the Scientific Review Section,
NIDR.  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 applications
under review, will be discussed, assigned a priority score, and 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 review, comments on the following aspects of the application will be made
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 the assignment of the overall score.

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 and Team:  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? Are multidisciplinary
expertise required to address the study questions represented on the team?

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?

The initial review will also examine the appropriateness of proposed budget and
duration, the adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects, the provisions for the protection of
human and animal subjects, and the safety of the research environment.

AWARD CRITERIA

The earliest anticipated date of award is September, 1998.  Applicants should be
aware that, in addition to scientific merit, program priorities and program
balance, the total cost of the proposed project and the availability of funds
will be considered by the NIDR and NIMH staff, the National Advisory Dental
Research Council and the National Advisory Mental Health Council in making
funding recommendations. In addition, the NIDR and NIMH value complementary
funding from other public and private sources including foundations and
industrial concerns.  In circumstances in which applications have similar
scientific merit, but vary in cost-competitiveness, the NIDR and NIMH are likely
to select the more cost-competitive for funding.

INQUIRIES

Written, email and telephone 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:

Eleni Kousvelari, D.D.S., MSc., DSc.
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 18A
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301) 480-8318
Email:  kousvelari@de45.nidr.nih.gov

Willo Pequegnat, Ph.D.
Office on AIDS
National Institute of Mental Health
Parklawn Building, Room 18-101
Rockville, MD  20857
Telephone:  (301) 443-9700
FAX:  (301) 443-9719
Email:  WPEQUEGN@NIH.GOV

Direct inquiries regarding grants management issues to:

Mr. Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  Martin.Rubinstein@nih.gov

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov

Schedule

Letter of Intent Receipt Date:  February 1, 1998
Application Receipt Date:       March 12, 1998
Scientific Review Date:         May-June 1998
Advisory Council Date:          August 1998
Earliest Award Date:            September 1998

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.121 and 93.242. 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 PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.


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