Full Text DE-94-003

ORAL MANIFESTATIONS OF HIV INFECTION

NIH GUIDE, Volume 23, Number 7, February 18, 1994

RFA:  DE-94-003

P.T. 34

Keywords: 
  Oral Diseases 
  AIDS 


National Institute of Dental Research

Letter of Intent Receipt Date:  April 1, 1994
Application Receipt Date:  May 6, 1994

PURPOSE

The National Institute of Dental Research (NIDR) invites research
grant applications to support research projects on the oral
manifestations of Human Immunodeficiency Virus (HIV) infection.
These projects encompass multidisciplinary, basic, clinical,
epidemiologic, and behavioral research designed to slow the spread of
acquired immunodeficiency syndrome (AIDS), to reduce the severity of
oral complications of HIV infection, and to minimize the effects of
HIV therapy.

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), Oral Manifestations of HIV Disease, is
related to the priority area of oral health.  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
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
non-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 (FIRST) Award (R29).  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms available for support of applications in response to
this RFA include research project grants (R01) and FIRST (R29)
awards.

FUNDS AVAILABLE

The NIDR will allocate approximately $2 million to support projects
from this RFA during FY 1994.  It is anticipated that at least eight
awards will be made, provided that applications are of sufficient
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.  Policies that govern research
grant programs of the National Institutes of Health will prevail.

RESEARCH OBJECTIVES

Background

The first cases of AIDS in the United States were reported as early
as 1981; however, 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.  Early in 1993, the World Health
Organization reported that 611,500 cases from 184 countries had been
recorded with over half of them coming from the United States.
According to the Centers for Disease Control and Prevention (CDCP),
from the time that AIDS was first reported in 1981 through the first
half of 1993, a total of 310,680 adult and adolescent AIDS cases and
179,748 deaths from AIDS had been reported in the U.S.   During 1992
alone, 47,106 AIDS cases were diagnosed and 29,763 deaths were
reported.  To date, nearly half of all AIDS cases reported have been
either African-Americans or Hispanics, although these groups combined
comprise only 21 percent of the U.S. population.

In January 1993, the CDCP adopted an expanded definition of AIDS that
took into account severe immunodepression, per se, and added
recurrent bacterial pneumonias, pulmonary tuberculosis and invasive
carcinomas in HIV-seropositive individuals to the long list of AIDS
defining conditions.  This expanded definition not only will increase
the absolute numbers of AIDS cases, but will likewise result in an
increase in the relative number of reported AIDS cases in females, as
well as in an increase in the number of individuals covered under the
expanded AIDS definition.  Another factor that will increase the
number of AIDS cases is the longer survival time resulting from
improved care and management of AIDS patients, which increases the
urgency for continuous treatment over longer periods of time.

Interest by the NIDR in AIDS, which dates back to shortly after the
disease was first identified, is based primarily on the prevalence
and severity of oral mucosal and gingival lesions, non-infectious
oral lesions, opportunistic infections, the importance of oral fluids
as sources of HIV inhibitory factors and as non-invasive diagnostic
tests for HIV.  In addition, two international workshops, partially
supported by the NIDR and devoted exclusively to the oral
manifestations of HIV infection, vividly point up the need for
continuing broad scale multidisciplinary studies to better understand
the natural history of the HIV and its oral manifestations in order
to minimize their devastating effects.

In the mid-1980s, it was learned that saliva is unlike other fluids
such as milk, tears, urine, and blood, in that HIV has rarely been
isolated from saliva.  NIDR intramural scientists, using saliva from
both normal volunteers and HIV patients, reported that in vitro
infectivity of monocytes in the presence of saliva was greatly
reduced and this finding might be attributed to salivary inhibitory
factors.  In July 1989, the NIDR issued an RFA (89-DE-2) titled
"Human Immunodeficiency Virus Inhibitory Factors in Human Saliva"  to
confirm findings of the NIDR investigators, and solicit studies to
identify, isolate and determine the mechanism of action of the
inhibitory factors in saliva.  Research resulting from this RFA has
shown that inhibitory factors are contained in high and low molecular
weight fractions.  The factors are specific for HIV, they act
rapidly, and their effectiveness falls off when diluted.  Further
research is needed to expand this information, particularly by
determining efficacy and mechanisms of action.

Early unpublished findings from other NIDR supported investigations
showed that HIV could be detected in gingival crevicular fluid (GCF),
particularly in sites with gingival inflammation.  The detection of
HIV in GCF could be made several months prior to the appearance of
HIV antibodies in the serum.  The detection of HIV antibodies in the
serum is generally regarded as the definitive proof of HIV infection.
However, HIV antibodies as well as the virus itself have been
demonstrated in limited amounts in saliva as well as in GCF, in many
cases before the demonstration of serum antibodies.  No studies have
determined the specificity, sensitivity and reliability of HIV
testing in saliva and GCF versus serum.  The earlier the detection of
the HIV or its antibodies, the earlier can intervention strategies be
begun and the oral complications minimized.  Saliva and GCF thus have
the potential for use as effective non-invasive HIV screening
procedures in large populations as well as in remote areas of the
U.S.A. and in third world countries.

A National Institute of Allergy and Infectious Diseases (NIAID)
sponsored national conference on HIV in women, in 1990, suggested
differences between males and females in the natural history of HIV
infection, including its oral manifestations.  However, due to
limited participation of women in AIDS clinical trials at that time,
it was not possible to confirm or refute this impression.  In
response, the NIAID organized the Women's Immunodeficiency HIV Study,
which is exploring clinical and psychosocial aspects of HIV infection
in women.  The NIDR is co-funding an oral component of this study to
obtain basic information on the oral manifestations of HIV infection
in women.  This RFA will expand this collaborative effort by
investigating the potential role of intrinsic growth factors and
hormones in the prevalence, frequency and severity of oral lesions in
HIV-infected women.  Studies are also sought to examine the
long-term, oral side-effects of therapy for HIV infection.
Additional investigations could focus on the impact of the mucosal
immune system in the transmission of HIV to unborn fetuses and
newborns.

HIV-infected individuals are reported to have an increased prevalence
of periodontal diseases.  Both gingivitis, an inflammation of the
gums, as well as periodontitis, which causes loss of bone and tissue
attachment to the tooth, have unique clinical features in
HIV-infected individuals.  For example, there are reports of
extremely aggressive forms of periodontitis in HIV infected patients
that lead to rapid and extensive destruction of the soft tissue and
bone exposure.  HIV-infected individuals with pre-existing
periodontitis tend to experience a higher rate of tooth attachment
loss compared with matched controls.  Histologically, the lesions in
HIV-infected individuals lack at least the CD4+ subsets of
T-lymphocytes.  The absence of regulatory and effector immune cells
may partially explain the rapidly progressive nature of periodontitis
in these patients.

In contrast to the evidence presented by some laboratories of an
increased susceptibility to periodontal disease with HIV infection,
there are reports that HIV-infected individuals exhibit healthy
periodontia and show no greater prevalence or severity of disease
than HIV-negative individuals.  Such findings imply that, despite
profound immunosuppression, HIV-infected patients have adequate
defenses against periodontal diseases.  This suggests that CD4+
T-lymphocytes may not be necessary to maintain a healthy
periodontium.  Studies are needed to explain these apparently
contradictory reports.  Studies are also needed on the pathogenesis
of periodontal diseases in HIV-infected individuals, the host immune
response and the unique histological features in these patients.
Reports of an increased risk of periodontitis in older persons and
women infected with HIV require further investigation and
clarification as well.  Levels of CD4+ cell counts appear to
influence the occurrence and severity of HIV-associated periodontal
manifestations.  GCF and circulating blood levels of CD4+ cells and
their subsets need to be related to the clinical stages seen in HIV
infection.  The temporal relationship between changes in CD4+ cell
counts and clinical manifestations likewise remains to be delineated.

Necrotizing gingivitis appears to be more common in HIV-infected
patients than in healthy individuals for unknown reasons.
Histologic, immunologic, bacteriologic and viral studies,
particularly for cytomegalovirus (CMV), are needed to characterize
possible risk factors for HIV-associated necrotizing gingivitis.  The
rate of periodontal attachment loss in HIV-infected persons needs to
be established in longitudinal studies.

A compromised immune system is the hallmark of HIV infection, AIDS,
and the associated opportunistic oral lesions.  To reduce the
severity of both AIDS and opportunistic oral lesions, it seems
logical to preserve and restore the integrity of the immune system.
However, from an epidemiologic perspective, the preferred approach to
controlling the spread of AIDS is to prevent exposure to the virus.
The development of an effective preventive strategy is essential
since an effective vaccine is at least ten years away according to
the IX International AIDS Conference in Berlin in June 1993.  Even
after an effective vaccine is developed, preventive strategies will
be needed.  Prevention programs must rely on solid research including
behavioral epidemiological studies of determinants of risk behaviors.
Controlled clinical trials of preventive intervention strategies are
needed to establish their effectiveness in reducing high-risk
behavior and incidence of disease. Further research is needed on
community-level interventions, behavior modification programs aimed
at prevention, maintenance of behavioral changes, and social and
behavioral issues in therapeutic and vaccine trials.

Research Areas of Interest

Some recommended research topics relevant to this RFA include, but
are not limited to:

o  Studies to fully characterize and determine the molecular
mechanisms of action of the HIV salivary inhibitory components.

o  Analytical studies of early and intermediate salivary markers of
HIV infection.

o  Studies to determine additional immunological factors, along with
T-cell defects, that contribute to the severe oral immunopathogenesis
associated with AIDS.

o  Investigation of the molecular events that transform Candida
albicans and other oral organisms from non-pathogenic to the
pathogenic forms; and the mechanisms of candidal adhesion to oral
tissues and to dental instruments.

o  Epidemiologic studies to determine if individuals who use illicit
drugs, alcohol, or tobacco singly, or in combination, have increased
susceptibility to oral HIV infection and the mechanisms by which
synergism might occur.

o  Studies of the pathogenesis of HIV-induced gingivitis and
periodontitis.

o  Comparative studies of the microbiota and oral opportunistic
lesions of seropositive and seronegative women.

o  Studies evaluating the reliability and usefulness of GCF and
saliva as potential diagnostic tools for non-invasive assessment of
HIV infection.

o  Epidemiologic studies to determine the extent to which ethnicity,
age, gender, education, economic status, access to care, and risk
behaviors influence development of oral manifestations of HIV
infection.

o  Knowledge, attitudes, and practices of oral health care personnel
on infection control, patient management, ethical issues, and
presenting complications of HIV infection.

o  Studies of neutrophil function in HIV-seropositive and
seronegative acute necrotizing ulcerative gingivitis patients.

o  Investigation of the transmission, or prevention of transmission,
of HIV in dental settings.

These areas of research are neither prioritized nor meant to be
restrictive.  Investigators are encouraged to submit scientifically
meritorious applications in any area of research responsive to the
general research objectives of this RFA.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them. This policy is intended to
apply to males and females of all ages. If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group. In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample site appropriate for the scientific objectives of
the study.  This information should be included in form PHS 398 (rev.
9/91) in items l-4 of the Research Plan and summarized in item 5,
Human Subjects.  Applicants are urged to carefully assess the
feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all such projects to include representation of the
full array of United States racial, ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, African Americans, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.  If the required information is not contained within the
application, the application will be deemed nonresponsive.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s), or justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and will be reflected in assigning
the priority score to the application.

All applications for clinical research submitted to the NIH are
required to address these policies. NIH funding components will not
award grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent by
April 1, 1994.  The letter should include a descriptive title of the
proposed research, the name, address and telephone number of the
principal investigator, the identities of other key personnel and
their participating institution(s), 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 to the NIDR staff in planning for timely
review of applications. It also allows NIDR staff to estimate the
potential workload and to avoid possible conflict of interest in
review.

The letter of intent is to be sent to Dr. Matthew Kinnard at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants are encouraged to consider collaborative arrangement with
investigators from other organizations.  Applicants from institutions
that 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.  If so, a letter
of agreement from either the GCRC program director of Principal
Investigator should be included with the application.

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301-435-0714; and from the program administrator listed
under INQUIRIES.

To identify the application as a response to this RFA, check "YES" on
item 2a of the face page of the application and enter RFA: DE-94-003,
"Oral Manifestations of HIV Infection".  The RFA label available in
the form PHS 398 must be affixed to the bottom of the face page of
the original application.  Failure to use this label could result in
delayed processing of an application such that it may not reach the
review committee in time for review.

Submit a signed, typewritten original of the application, including
the checklist, and three signed, photocopies, by May 6, 1994 in one
package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

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

H. George Hausch, Ph.D.
Extramural Program
National Institute of Dental Research
Westwood Building, Room 519
Bethesda, MD  20892

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NIDR program staff function.
Applications that are considered non-responsive will be returned by
the NIDR, but may be submitted as investigator-initiated research
project grants at the next receipt date.

Applications that are complete and responsive may be subjected to a
triage by a peer review group to determine their scientific merit
relative to the other applications received in response to the RFA.
The NIH will withdraw from competition those applications judged to
be noncompetitive and notify the applicant and institutional business
official.  Applications judged to be competitive will be further
evaluated for scientific/technical merit by a special grants review
committee convened by the NIDR Scientific Review Office.  Secondary
review will be by the National Advisory Dental Research Council.

Major factors to be considered in the evaluation of applications
include:

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly but not exclusively in the area
of the proposed research;

o  availability of resources necessary to perform research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

AWARD CRITERIA

The anticipated date of award is September 30, 1994.  Applicants will
compete for available funds with all other recommended applications
and should be aware that, in addition to scientific merit, program
priorities, program balance, the total cost of the proposed project
and the availability of funds will be considered by NIDR staff and
the 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.

INQUIRIES

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 and address the letter
of intent to:

Dr. Matthew A. Kinnard
Oral Soft Tissue Diseases and AIDS Program
National Institute of Dental Research
Westwood Building, Room 509
Bethesda, MD  20892
Telephone:  (301) 594-7641
FAX:  (301) 594-9720

Inquiries regarding fiscal matters may be directed to:

Ms. Theresa Ringler
Grants Management Office
National Institute of Dental Research
Westwood Building, Room 510
Bethesda, MD  20892
Telephone:  (301) 594-7629
FAX:  (301) 594-7600

Inquiries regarding review issues may be directed to Dr. George
Hausch at the address listed under APPLICATION PROCEDURES.

AUTHORITY AND REGULATIONS

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
review.

.

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