Panel on AIDS Research
Final Report
December 10, 2002
Sponsored by:
The National Institute of Dental and Craniofacial Research
National Institutes of Health
I. Background:
The National Institute of Dental and Craniofacial Research (NIDCR) is the
primary sponsor of biomedical and behavioral research and research training
in dental,
oral and craniofacial diseases and disorders in the United States. The mission
of the Institute is to promote and improve health through research. It accomplishes
its mission by supporting research and training programs in intramural laboratories
and in an extended community of investigators working in academic institutions
and other research organizations.
Research on the oral aspects of HIV/AIDS is
part of the science support portfolio of NIDCR. Recognizing the importance
of identifying long-term scientific opportunities
in this area, NIDCR convened an expert panel on December 10, 2002, to identify
opportunities for significant scientific advances in oral AIDS research.
The panel
is part of a series of expert advisory groups that have been convened in
the last few months to help NIDCR review scientific opportunities in several
broad
areas
of science, including genomics/proteomics, the repair and regeneration of
tissues, clinical research and training. The final reports from these previous
panels
are
posted or will shortly be on the NIDCR web page (http://www.nidr.nih.gov/research/long_range_research_opps.asp).
The panelists were provided with background information, including the current
AIDS research portfolio, relevant recent NIDCR-sponsored requests for applications
(RFAs) and relevant publications and were asked to identify broad areas
of research
opportunity for a period of 5-10 years.
II. General Discussion
The Director of NIDCR, Dr. Lawrence Tabak, opened the meeting by thanking
the panel members and by indicating how important the discussion will be in
charting
the Institute’s course in supporting research in this area. The last meeting
of this type was held in 1997 and although many of the goals recommended at
that
time have been accomplished, significant challenges remain to be addressed. The
widespread use of highly active AIDS retroviral therapy (HAART) and other therapies
has added another dimension of health effects to address. There have also been
some advances in basic science that suggest new avenues for investigation. NIDCR
wants to ensure that its resources for AIDS research are spent as wisely as possible
in the future by funding areas of investigation that can move the field forward.
They may include areas that are considered “high risk” but with potential
“high impact” outcomes.
NIDCR has also begun to prioritize areas
of research and identify the areas of high priority. The panel was asked to
do a similar exercise and provide the Institute
with a “priority list” in AIDS research that includes the areas
of
high opportunity.
Dr. Dennis Mangan, Chief of the Infectious Diseases and Immunology
Branch of the Division of Basic and Translational Sciences, NIDCR reviewed
the background
information
provided to the panelists. The 1997 ad-hoc panel meeting made several recommendations,
including to study oral transmission in more detail and to evaluate the opportunistic
infections occurring in the oral cavity
(www.nidcr.nih.gov/about/strat-plan/aids.asp).
The group also recommended studying mucosal immunity and the development of
vaccines
that can be delivered through the mucosal surfaces of the oral cavity. There
was reference to therapeutics, to behavioral and social sciences and to training
new
investigators in all these areas of research. Several requests for applications
(RFAs) were issued in response to the advice of the group (in oral transmission,
mucosal immunity and opportunistic infections). In 2002, an ad-hoc panel of
experts
identified 5 main areas of research opportunity in oral AIDS: epithelial cell
biology, diagnosis, AIDS in special populations, the molecular interactions
between
the virus and compartments in the oral cavity and AIDS-related malignancies.
The background information provided to the panel included a description of
the current support portfolio of 60-70 projects for a total of $23-24 million
in fiscal
year 2002. At present, there are 2 additional RFAs out, the first on innate
mucosal immunity and the second on oral mucosal vaccination against HIV infection
and
related opportunistic infections. Successful grant applications are to be funded
in fiscal year 2004. In addition, plans are underway to support a multi-center
clinical trial testing the application of topical thalidomide for the treatment
of oral lesions in HIV/AIDS patients and a study of AIDS-related oral malignancies
and tumors.
Adding Oral Components to Clinical Trials
The panel suggested
that integration of oral health components in on-going medical clinical trials
would provide needed data on oral health. Nesting a
study on oral
health in the next Aids Clinical Trials Group (ACTG) large antiretroviral study
is an example of this type of interaction. Using this type of study to undertake
specific genomic research efforts related to the risk of oral complications
in
antiretroviral therapy is another example. This approach also lends itself
to the study of the effects of HAART on salivary gland function (the flow and
composition
of saliva) and its implications for the development of oral disease. An oral
component can also be added to on-going clinical trials with reasonable primary
end points
(i.e., 2 years) on which patients are being followed at 4-month intervals and
have well documented histories of antiretroviral therapy. Although these trials
do not likely have base line data on oral health questions, they may still
be
useful by building on the available history of the population under study.
Focusing
on Population-based Studies
Cohort studies and other population-based studies can be viewed as
opportunities to advance the understanding of the etiology and pathogenesis
of the oral manifestations
of HIV/AIDS and their relationship to disease progression, particularly if
one considers an expansion into the international arena. There is a lot of
untreated
natural history in Africa and Asia primarily involving individuals who have
no or little access to therapy. This situation is about to change to some extent
with the gradual introduction of antiretroviral therapy. It would be beneficial
to partner with scientists from these areas to investigate what kinds of oral
lesions may be specific to these regions and to study the effects of interventions
on the scope and extent of these pathologies. Population-based research can
also
provide an opportunity to introduce and apply genetics and genomics, in terms
of assessing disease risk and susceptibility to pathogen-specific diseases.
An
example would be the relationship between HLA haplotype and the risk for aphthous
ulcers.
The panel agreed that there are gaps in knowledge in the pediatric population
because the studies to date have focused on have involved only a few descriptive
variables. Additional research on oral transmission after breast-feeding is
needed
to understand why only 25% of the babies who are breast-fed by HIV positive
mothers acquire HIV infection. It was recognized that the logistics for these
studies
are complicated and the infrastructure is limited.
Applying Salivary Diagnostics
Another area of opportunity
is the use of saliva to monitor drug exposure, compliance with therapy, disease
progression and successful outcomes of therapy.
Investigations
can also address issues of drug absorption and pharmacokinetics using saliva.
Understanding
HIV Compartmentalization and Oral Mucosal Immunity
The compartmentalization
of HIV in the oral cavity is not well understood. How co-infections or prior
exposure to other organisms affect susceptibility
to HIV
also requires further study. Research is needed to establish why the oral mucosa
is apparently more resistant to HIV than the rectal and vaginal mucosa. The
presence
of potential inhibitory factors (thrombocytin, SLPI, etc.) in saliva and the
comparison of the phylogenetic structures of viral populations in oral secretions
and in
blood and lymphoid tissues can be other areas of research interest. There is
a large amount of SLPI in the newborn saliva and salivary gland, but we do
not know
a lot about the mucosal immune system in the newborn. There may be unique sequences
in the virus isolated from the oral cavity, as compared with other mucosal
sites.
The oral cavity has been considered as a “unique” reservoir, since
it has been suggested that viral levels there do not decrease after HAART,
as
do the levels in peripheral blood.
Not enough is known about the oral flora
in the newborn, but it probably changes once teeth start erupting.
Other
areas of interest and opportunity are comparative virology (i.e., HIV vs.
other viruses that are transmitted orally and that cause oral disease)
and comparative
immunology (i.e., between different mucosa). The oral cavity can perhaps
be used as a surrogate for genital or rectal mucosa to study response to
vaccines
and
vaccine approaches.
III. Recommendations
The panel was asked to identify research areas in which NIDCR could take
the lead and stimulate research that is pertinent to its mission of improving
oral
health.
After extensive discussion, the panel identified the following areas
of opportunity for NIDCR:
- Studies to obtain an enhanced understanding of
the basic biology of innate and adaptive immune responses in the oral cavity
and the effect
of commensal
bacteria
and of co-infecting viruses. Specific investigations should focus on:
- structural
and functional differences between the oral mucosa and other mucosae
- specific
elements in the oral mucosa that prevent HIV transmission and the role
of other oral pathogens
- the cells that are initially infected and what
cell components (i.e., cell receptors) interact with the virus (fundamental
questions of viral
pathogenesis
in the oral cavity)
- identifying components of the immune system that may
control the virus
- elucidating compartmentalization of HIV (comparing mucosal
compartments) in the oral cavity
- the role of oropharyngeal lymphoid
structures, particularly the tonsils
- oral measures of osteoporosis as
a complication of HAART
The panel recommended the use of animal models to study mucosal immune responses
using models that have been created by others to work on oral HIV issues
of
interest to the Institute.
- Application of tissue engineering, to create surrogate
models in tissue culture that can complement animal models.
- Application of
genomics and proteomics, to study tissue specific gene expression in the
oral cavity and to link this information with the genomics of the viruses
and bacteria.
- Trafficking of immune and epithelial cells and the comparative
turnover of virus in the oral and systemic compartments. The basic molecular
mechanisms
that brings the virus back to the oral cavity (i.e., a “homing” signal
in the cells).
- Using on-going clinical trials to look at oral aspects of HIV/AIDS.
These can be tapped to study issues of
- natural history of oral HIV, notably but not exclusively the value
of oral lesion incident events as indicators of treatment failure and
onset of viral
resistance. The nature and significance of the oropharyngeal lesions
of acute/primary HIV infection are not fully documented or understood.
- epidemiology
of complications/lesions, such as changes in the type or expression
of oral lesions in the presence of antiviral therapy, including confirmation
of reports of the development of papilloma virus/warts lesions
- pathogenesis
of infectious and auto immune complications such as candidiasis, hairy
leukoplakia, warts, aphthous ulcers and other lesions
- oral immune reactions,
particularly the role of dendritic cells
- effects of treatment on oral
lesions (i.e., oral warts and other lesions)
- changes in salivary flow
and composition in response to HAART and other therapies
- oral measures
of osteoporosis as a complication of HAART
- Studies of the reactivation of HPV infection as part of the immune
reconstitution syndrome in people receiving HAART therapy. These studies
should elucidate
the
signals involved and can be tied in with the tissue engineering models and
with studies of genetic susceptibility in various subtypes of responders
and non-responders
(progressors). The appearance of oral warts is associated with therapeutic
success and may be more common in men than in women. The same is true of
hairy leukoplakia.
HPV may play a role in oral cancer and current work on a HPV vaccine may
not apply necessarily to the oral environment because oral subtypes are different
from genital subtypes.
- The role of previous infection with Candida albicans
and other Candida species
in facilitating the transmission of HIV. This could be investigated in newborns
and extended to a study of the role of any form of oral lesion in modifying
transmission.
- Issues of dental caries and periodontal disease and the changes,
if any, occurring after HAART therapy.
- The overall oral care needs of the
HIV/AIDS populations in the U.S. and developing countries.
- The frequency
and nature of salivary gland disease in HIV infection and the changes in
salivary function during HAART therapy and how it relates to
Sjogren’s syndrome.
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