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
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. 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.