Full Text DE-96-003
NIH GUIDE, Volume 25, Number 1, January 26, 1996
RFA:  DE-96-003
P.T. 34

  Infectious Diseases/Agents 

National Institute of Dental Research
Letter of Intent Receipt Date:  March 26, 1996
Application Receipt Date:  April 26, 1996
The National Institute of Dental Research (NIDR) invites applications
from biomedical and behavioral investigators designed to advance an
understanding of the underlying mechanisms i.e., molecular, genetic
and behavioral, that result in the development of oral complications
associated with HIV-infection and AIDS.  The overall goal of this RFA
is to encourage research aimed at developing state-of-the art
biomedical and behavioral methodologies for the prevention and
treatment of these pathologies.  Since the current AIDS grant
portfolio of the Institute is already supporting a large number of
epidemiological studies as well as studies on the basic biology of
candida, additional applications on these topics is discouraged.
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,
"Underlying Mechanisms of Oral Manifestations of HIV Infection" 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 "Healthy People 2000" (Summary Report: Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Office, Washington, DC 20402-9325 (telephone 202-783-3238).
Applications may be submitted by domestic and foreign, non-profit and
for-profit organizations, public and private, such as universities,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  Foreign institutions
are not eligible for the First Independent Research Support and
Transition Award (FIRST) (R29).  Applications from minority and women
scientists are encouraged.
Support of this program will be through the National Institute of
Dental Research.  The mechanisms available for support of
applications to this RFA include research project grants (R01) and
FIRST (R29) awards.
The NIDR will allocate approximately $2 million to support projects
from this RFA during FY 96. It is anticipated that at least eight
awards will be made, provided that applications are of high
scientific merit.  Applicants may request up to five years of
support. Subsequent support will be dependent upon submission by the
applicant of a renewal application through established NIH procedures
for research grants related to AIDS.  Although this program is
provided for the financial plans of NIDR, the award of grants
pursuant to this RFA is contingent upon availability of funds for
this purpose.  Policies that govern research grant programs of the
National Institutes of Health will prevail.
The AIDS pandemic continues to grow worldwide despite sustained
efforts by scientists and health care workers along with the
commitment of considerable resources.  Progress in minimizing the
spread of this public health menace has been slower than anticipated.
By the year 2000, the World Health Organization (WHO) estimates that
between 30 and 40 million people will be infected with HIV.  In the
United States, one person dies of AIDS every 8 minutes, and the rate
is increasing in women as well as in African American and Hispanic
AIDS is a severe T cell immunodeficiency caused by infection with
HIV.  During the last few years, it was discovered that this RNA
virus has a significant rate of mutations, thereby producing various
forms of HIV pathogenesis. The major viral form has a tropism for
monocytes and CD4+T lymphocytes causing depletion of these cells by
direct lysis as well as via several indirect mechanisms that lead to
death, defective maturation, and abnormal function of uninfected T
cells.  The depletion of T cells and acquired alterations in other
cell functions result in greatly increased susceptibility to
infection by a number of opportunistic microorganisms, including
bacteria, fungi and viruses.
The NIDR is currently supporting research projects to identify and
treat oral pathologies associated with HIV infection and progression
to AIDS in all patient groups.  The AIDS research program of the NIDR
includes studies involving:  the prevalence and severity of oral
mucosal and gingival lesions; non-infectious oral lesions; the
importance of oral fluids as sources of HIV inhibitory factors and
non-invasive diagnostic tests for HIV; the etiology, natural history
and epidemiology of AIDS; the oral component of the Women~s
Interagency HIV study (WIHS); searches for oral diagnostic markers;
investigations of the molecular events that transform candida and
other oral organisms from non-pathogenic to pathogenic forms; and the
development of new therapeutic strategies to combat reoccurrence of
candida infections.  Other studies include research on oral mucosal
immunity, salivary leukocyte protease inhibitor (SLPI), development
of synthetic vaccines and drug delivery systems, the use of
transgenic mice, and other methods to elucidate the effect of HIV
infections on selected tissues.
Characterization of inhibitory salivary proteins.
As early as the mid-1980s it was recognized that HIV is rarely
isolated from saliva.  Infectivity of lymphocytes in the presence of
saliva is greatly reduced in vitro. These findings were attributed to
salivary inhibitory factors.  Data from previous and current projects
show that inhibitory factors are contained in high and low molecular
weight fractions. Inhibitory activity in parotid secretions is
associated with four components that bind specifically to recombinant
gp120. Major inhibitory activity was found in a 37kDa protein.
Partial characterization of this latter protein suggests that it may
be the parotid-specific basic proline-rich protein, PS1.  Factors
unique to submandibular/sublingual secretions, such as mucins, appear
to function in viral particle entrapment.  Evidence suggests that in
whole saliva at least two mechanisms, aggregation and agglutination,
may be responsible for inhibition of HIV infectivity.  Recently, SLPI
has been reported to exhibit inhibition of HIV infectivity in vitro
at physiological concentrations. In addition, data from current
projects indicate that saliva contains low molecular weight molecules
called histatins with anti-candida activity.  Histatins have shown to
be reduced in saliva of HIV infected persons. One of the goals of
this RFA is to develop methods to enhance the biological activity of
the salivary proteins with anti-candida and anti-HIV activities in
the oral cavity as a way to increase the host~s defense capabilities.
To fulfill this goal, additional research is needed to isolate and
characterize the genes and protein structures of the salivary
proteins which serve as candidates to exhibit anti-candida and anti-
HIV activities.
Molecular mechanisms underlying HIV-associated immunosuppression.
The oral complications of HIV infection have been considered an
initial manifestation of infection in high-risk patients for HIV as
well as an important marker for the disease progression.  The oral
lesions manifested by HIV infection may be associated with specific
pathogens, including fungi, bacteria and viruses.  NIDR has initiated
a number of studies of the elucidation of AIDS-related opportunistic
infections particularly involving candida as an AIDS-related
pathogen.The goals of these studies were to elucidate the basic
biology and pathogenic mechanisms of candida species.  However, it is
becoming clear that oral candidiasis, hairy leukoplakia (Epstein-Barr
virus, EBV) and reactivation of human cytomegalovirus (HCMV), herpes
simplex virus (HSV) and human papillomavirus (HPV) are manifestations
within a complex series of inflammatory and immune responses to HIV
infection.  Additional research is needed to elucidate the molecular
mechanisms by which HIV or HIV-associated immunosupression might
affect the phenotypic variability and pathogenesis of candida and the
reactivation of HCMV, HSV, HPV and EBV.
Mechanisms of retrovirus infection in exocrine tissue.
Early in the AIDS pandemic it appeared that HIV-infected persons may
have shared clinical symptoms of salivary gland dysfunction with
patients with autoimmune disease.  HIV associated salivary gland
disease is defined as the presence of enlargement of the major
salivary glands and diminished salivary function in some HIV infected
individuals. It has a number of similarities as well as differences
from Sjogren~s syndrome (SS).  For example, SS patients often exhibit
polyclonal gammopathy  which is also present in AIDS.  T cell defects
and autoantibodies occur in both SS and AIDS patients, however, CD4+T
cells are the predominant infiltrating cells in SS, whereas CD8+T
cells dominate the salivary infiltrate in HIV-associated salivary
gland disease.  This manifestation of HIV infection seems to reflect
host immune response associated with the salivary glands and lungs.
In view of the considerable clinical overlap between SS and AIDS, at
least at the early stage of infection, minor salivary gland biopsies
from both patient groups can be used to elucidate the mechanisms of
retrovirus interactions with exocrine tissues along with their
differences and/or similarities with autoimmune disease.  Thus, not
only is the study of the role of HIV infection in salivary gland
function important in its own right but it also could offer an
excellent model system to study the progression of the disease in
exocrine glands.
Oral mucosal immunity and HIV infection.
Increases in oral infections associated with HIV infection provide
opportunities to investigate the oral mucosal immune responses that
provide protection against HIV-associated opportunistic infections in
the mouth. The mucosal immune system is generally characterized by
the predominance of IgA in external secretions, and in IgA producing
plasmacytes in tissues underlying mucosal epithelium as well as
within certain excretory glands, i. e., salivary glands. In the oral
cavity, secretory IgA is synthesized by the major and minor salivary
glands. It has been shown that IgA-committed cells travel from
gastrointestinal and other lymphoid tissues (GALT) to glandular
mucosal tissues such as salivary, lachrymal and mammary glands.
These cells also go from GALT to the lamina propria of small
intestine, bronchiae and vagina, thus establishing the mucosal immune
network.  Secretory IgA (SIgA) is believed to neutralize some types
of viruses more effectively than serum IgA.  Its polymeric structure,
its presence in mucus secretions, and its resistance to proteolytic
degradation are often described as factors which may contribute to a
more effective neutralizing ability.  It has been shown that as HIV
infection advances, there are variations in serum IgA and SIgA
levels.  Total non-specific SIgA levels often decline while, total
non-specific serum IgA levels often increase dramatically.  This is
suggestive of selective deregulation of IgA production and transport.
Changes in IgA modulation may be reflective of alterations in mucosal
immunity induced by HIV.  The mechanisms responsible for the
regulation of serum IgA and SIgA in HIV infection need further
investigation. Cytokines are responsible for switching of IgA
isotypes as well as migration of IgA producing cells to the lamina
propria.  Correlation of cytokine profiles and levels in the oral
tissues of HIV infected and healthy persons may provide information
on the role of cytokines on the deregulation of IgA production and
Behavioral research on oral manifestations of HIV infection.
Epidemiological studies have indicated that AIDS can be prevented
with changes in lifestyle or behaviors which limit transmission of
the virus.  Behaviors engaged in by patients and health care
providers also influence the detection, prevention, and treatment of
oral manifestations of HIV infection. Since oral manifestations of
HIV infection tend to occur early, access to health care providing
accurate detection of oral changes associated HIV infection, could
lead to earlier referral to appropriate health care providers and
possibly improve therapeutic outcomes.  Few studies have determined
behavioral/educational strategies to enhance early detection of oral
indicators of HIV infection manifestations, or have assessed specific
factors impeding oral self-examination or professionals~ detection of
HIV-associated oral changes. Behavioral studies in these areas are
Similarly, few studies have assessed the effects of oral
manifestations of HIV infection on patients~ adherence to therapeutic
regimens, quality of life, functional status, pain experience, and
rehabilitation.  Assessing the effects of HIV-related oral changes
and specific oral therapies on functional outcome measures could
contribute valuable insights on preventive or therapeutic strategies
yielding outcomes which directly and demonstrably benefit the HIV
Research Objectives and Scope
The goal of this RFA is to encourage basic research into the
mechanisms of HIV infection and subsequent pathogenesis to understand
the oral complications associated with AIDS.  In addition, critical
studies are needed to develop strategies for biomedical and
behavioral approaches to prevent and reduce the severity of these
pathologies.  The oral cavity presents an excellent model for
investigations on the pathological effects of HIV because of frequent
manifestations of HIV infection in the mouth, easy access for
specimen collection, a reflection in the oral cavity of alterations
in the immune function at distant mucosal sites, and availability of
information about the effects of viruses, particularly through
infectious changes, on the mucosal immune system.
This RFA is intended to stimulate further scientific investigations
on the underlying molecular and genetic mechanisms that allow the
development of oral complications associated with HIV-infection and
AIDS as well as to develop state-of-the-art methodologies for the
prevention and treatment of these pathologies.
Some recommended research topics are provided as examples and are not
intended to be inclusive or restrictive:
o   determination of genes and protein structures and elucidation of
the molecular mechanisms of action of the salivary inhibitory
o   use of NMR spectroscopy, X-ray crystallography and computer
programs to model biologically active peptide regions that have
implications for anti-candida and anti-HIV activities;
o   construction of bioactive synthetic peptides and recombinant
proteins of the salivary proteins that have been identified as having
anti-candida and anti-HIV activities and development of systems for
their delivery;
o   identification and elucidation of the molecular changes induced
in the oral environment by HIV that can affect the phenotypic
variability of candida and the reactivation of HCMV, HSV, HPV and
o   examination of the changes in the minor salivary glands and
elucidation of the mechanisms underlie salivary gland pathogenesis in
HIV-infected individuals (particularly, the mechanisms leading to the
CD8+ T cell infiltrate in HIV-infected individuals as well as studies
in understanding the function(s) of these lymphocytes in salivary
gland injury);
o   delineation of the mechanisms of oral genetic factors that
mediate resistance or sensitivity to infection and influence disease
progression (e.g. HLA-controlled immune responses to HIV and self
antigens; HIV modulated cytokine responses);
o   use of immune deficient mice as a model to analyze host-virus
interactions on mucosal surfaces and in the salivary glands and to
outline the specific immune mechanisms that are important for
inherited or acquired resistance to oral infections or to salivary
gland pathologies;
o   development and use of existing innovative and highly sensitive
molecular techniques such as in situ PCR, mimic PCR, flow  cytometry
and ELISPOT, to examine changes in cytokines, other immune regulators
and cellular levels of immunoglobulins in saliva and in oral
o   examination of the local (oral) immune responses in HIV-
seropositive and HIV-seronegative individuals by making use of
saliva, oral biopsies (e.g., minor salivary glands, mucosal cells)
which are easy to sample and represent a unique aspect in monitoring
diseases at the site of the tissue under attack and comparisons with
other mucosal sites;
o   quantitation of salivary SIgA, serum IgA and cytokine levels at
the different stages of HIV infection and correlation with the
pathogenesis of oral manifestations of HIV infection;
o   development of recombinant methodologies and adjuvants for the
enhancement of SIgA in saliva;
o   development and evaluation of strategies for influencing members
of high-risk groups, patients, and health care providers to adopt
behaviors which improve early detection, prevention and treatment of
oral manifestations of HIV infection, thus contributing to the early
detection, prevention, and treatment of HIV infection; and
o   development of knowledge providing the basis for improving
quality of life, adherence to treatment protocols and functional and
health outcomes in patients with oral manifestations of HIV
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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
concerning the inclusion of minorities in study populations which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
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 reprinted
in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18,
1994.  Investigators may obtain copies from these sources or from the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
Prospective applicants are asked to submit, by March 26, 1996, a
letter of intent.  This should include the number and title of this
RFA, a descriptive title of the proposed research, the name,
addresses, and telephone number of the Principal Investigator, the
identities of other key personnel and participating institutions, the
number of the RFA DE-96-003, and the title "Underlying Mechanisms of
Oral Manifestations of HIV Infection."
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 allows 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.
Prospective applicants are encouraged to communicate with program and
grants management staff of the NIDR's Division of Extramural Research
as early as possible in the planning phase of application
preparation.  Advice and suggestions by staff may materially assist
applicants to ensure that the objectives and structure and the budget
format are acceptable.
Applications must be prepared on form PHS 398 (Rev. 5/95).  An
Application for a PHS Grant is available at most institutional
business or grants and contracts offices and may be obtained from the
Office of Grants Information, Division of Research Grants (DRG),
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892 (Telephone: 301-710-0267).  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
"Underlying Mechanisms of Oral Manifestations of HIV Infection."
"DE-96-003" must be typed in item 2 of the face page of the
application form and the YES box must be checked.
Applications of the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application. FIRST Award (R29) applications, submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
Applicants from institutions which have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research. In such a case, a letter of agreement from
either the GCRC program director or principal investigator should be
included with the application.
Submit a signed, typewritten original of the application, including a
cover letter (if appropriate), the checklist, and three signed
photocopies, in one package to:
Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040
Bethesda, MD 20892 (use 20817 for Federal Express)
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
Natcher Building, Room 4AN-38D
Bethesda, MD 20892-6402
Applications must be received by April 26 , 1996. If an application
is received after that date, it will be returned to the applicant
without review.
Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NIDR. Incomplete applications will be
returned to the applicant without further consideration. If NIDR
staff find that the application is not responsive to the RFA, it will
be returned without further consideration.  Remaining applications
may be subjected to a streamlined review process by a special grants
review committee convened by the NIDR Scientific Review Office, to
determine their scientific merit relative to other applications
received in response to the RFA.  The NIDR will withdraw applications
judged to be in the bottom tier of applications.  Applications
determined to be competitive will be evaluated for scientific and
technical merit by the review committee.  Secondary review of the
applications will be conducted by the National Advisory Dental
Research Council.
Major factors to be considered in the evaluation of the applications
o   the extent to which research project will broaden and strengthen
the scientific base underlying the national capability to improve
oral health;
o   the scientific merit of the proposed research project, including
its  significance, originality, feasibility, and experimental design;
o   qualifications and research experiences of the Principal
Investigator and staff, particularly but not exclusively in the area
of the proposed research;
o   the scientific/technical merit and justification for requested
resources; and
o   the ability to recruit individuals from appropriate study
populations (i.e.,  women, subpopulations of minorities and disabled
individuals) as defined by the NIH guidelines along with provisions
for their protection from research risks and the humane treatment of
animal research subjects that may be used.
The earliest anticipated date of award is September 30, 1996.
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 staff and the National Advisory Dental Research Council in
making funding recommendations. In addition, the NIDR appreciates the
value of 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 is likely to select the more
cost-competitive application for funding.
Written 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:
Dr. Eleni Kousvelari
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
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
Email: Martin.Rubinstein@NIH.GOV
This program is described in the Catalog of Federal Domestic
Assistance No. 93. 121.  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
The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

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