Advances in Dental Research recent issues

Preface

ten Cate, J.M. B. — 2009-08-07

Remineralization, the Natural Caries Repair Process--The Need for New Approaches

Featherstone, J.D.B. — 2009-08-07

The Need for Antibacterial Approaches to Improve Caries Control

ten Cate, J.M. B. — 2009-08-07

Dental Erosion--Novel Remineralizing Agents in Prevention or Repair

Lussi, A. — 2009-08-07

Opportunities for Disrupting Cariogenic Biofilms

2009-08-07

Dentin Hypersensitivity, the Biofilm and Remineralization: What is the Connection?

Wolff, M.S. — 2009-08-07

Casein Phosphopeptide-Amorphous Calcium Phosphate: The Scientific Evidence

Reynolds, E.C. — 2009-08-07

RecaldentTM--Evidence for Clinical Activity

Zero, D.T. — 2009-08-07

Calcium Sodium Phosphosilicate (NovaMin(R)): Remineralization Potential

Burwell, A.K., Litkowski, L.J., Greenspan, D.C. — 2009-08-07

NovaMin(R): Likely Clinical Success

Wefel, J.S. — 2009-08-07

Xylitol and Its Vehicles for Public Health Needs

Milgrom, P., Ly, K.A., Rothen, M. — 2009-08-07

Current Controversies -- Is There Merit?

Twetman, S. — 2009-08-07

Achieving Probiotic Effects via Modulating Oral Microbial Ecology

He, X., Lux, R., Kuramitsu, H.K., Anderson, M.H., Shi, W. — 2009-08-07

Antimicrobial Peptides for Plaque Control

2009-08-07

Naturally Occurring Molecules as Alternative Therapeutic Agents against Cariogenic Biofilms

Koo, H., Jeon, J. G. — 2009-08-07

Can the Ecology of the Dental Biofilm Be Beneficially Altered?

Beighton, D. — 2009-08-07

Xylitol, Mutans Streptococci, and Dental Plaque

Soderling, E.M. — 2009-08-07

Challenges of Implementing New Remineralization Technologies

Pfarrer, A.M., Karlinsey, R.L. — 2009-08-07

Remineralization/Desensitization: What Is Known? What Is the Future?

Pitts, N.B., Wefel, J.S. — 2009-08-07

Antibacterial and Probiotic Approaches to Caries Management

Adair, S.M., Xie, Q. — 2009-08-07

Introduction

Gonzalez-Cabezas, C. — 2008-07-01

Evidence-based Effectiveness of Topical Fluorides

Marinho, V.C.C. — 2008-07-01

Is Water Fluoridation Still Necessary?

Kumar, J.V. — 2008-07-01

How to Maintain a Cariostatic Fluoride Concentration in the Oral Environment

Cury, J.A., Tenuta, L.M.A. — 2008-07-01

Strategies to Enhance the Biological Effects of Fluoride on Dental Biofilms

Koo, H. — 2008-07-01

Introduction

Coogan, M., Hodgson, T., Challacombe, S. — 2006-04-01

The Phuket Declaration

2006-04-01

Overview and Research Agenda Arising from the 5th World Workshop on Oral Health and Disease in AIDS

Challacombe, S., Coogan, M., Williams, D., Greenspan, J. — 2006-04-01

HIV Pathogenesis: Knowledge Gained after Two Decades of Research

Levy, J.A. — 2006-04-01

Great progress has been made in our understanding of HIV since its initial discovery about 20 years ago. The ability of HIV to infect CD4⁺ lymphocytes and a wide variety of other cells in the body is appreciated, as is its role in immunologic, gastrointestinal, and brain disorders. HIV enters cells via the CD4 molecule, chemokine co-receptors (CXCR4, CCR5), and other cell-surface proteins. Several accessory virus-associated genes (e.g., Rev, Tat, Nef) have uncovered unique pathways that can also be observed in normal cells. Recently, the discovery of natural cellular resistant factors (APOBEC3G and TRIM5a) has provided avenues for novel antiviral therapies. Studies of long-term survivors have given insight into immune responses that control HIV and can prevent infection. Neutralizing antibodies and CD8+ cell cytotoxic responses, as well as plasmacytoid dendritic cells and CD8+ cell non-cytotoxic antiviral responses, are adaptive and innate immune activities mediating this anti-HIV effect. HIV vaccine studies have indicated that conventional approaches do not work against this integrated intracellular parasite. While much has been learned about HIV, more details are needed about its infection cycle and its pathologic effects in the body. The past 20 years have yielded important information on HIV/AIDS that should lead to effective anti-HIV therapies and a vaccine.

Policy for Prevention of Oral Manifestations in HIV/AIDS: The Approach of the WHO Global Oral Health Program

Petersen, P.-E. — 2006-04-01

The HIV/AIDS pandemic has become a human and social disaster, particularly affecting the developing countries of Africa, Southeast Asia, and Latin America. By the end of 2004, about 40 million people were estimated to be infected by HIV globally. The health sectors in many affected countries are facing severe shortages of human and financial resources, and are struggling to cope with the growing impact of HIV/AIDS. In most developed countries, the availability of antiretroviral treatment has resulted in a dramatic reduction in HIV/AIDS-related mortality and morbidity. In contrast, in the developing countries, there is little access to treatment, and access to HIV-prevention services is poor. The ’3 by 5' initiative was launched by the WHO and UNAIDS in 2003 with the aim of providing antiretrovirals to three million people in developing countries by the year 2005. HIV infection has a significant negative impact on oral health, with approximately 40–50% of HIV-positive persons developing oral fungal, bacterial, or viral infections early in the course of the disease. Oral health services and professionals can contribute effectively to the control of HIV/AIDS through health education and health promotion, patient care, effective infection control, and surveillance. The WHO Global Oral Health Program has strengthened its work for prevention of HIV/AIDS-related oral disease. The WHO co-sponsored conference, Oral Health and Disease in AIDS, held in Phuket, Thailand (2004), issued a declaration calling for action by national and international health authorities. The aim is to strengthen oral health promotion and the care of HIV-infected persons, and to encourage research on the impact that HIV/AIDS, public health initiatives, and surveillance have on oral health.

Innate and Adaptive Mucosal Immunity in Protection against HIV Infection

Bergmeier, L.A., Lehner, T. — 2006-04-01

The appalling toll on the populations of developing countries as a result of the HIV epidemic shows no signs of abatement. While costly drug therapies are effective in developed nations, the sheer scale of the epidemic elsewhere makes the need for a vaccine an ever more urgent goal. The prevalent DNA prime-viral boost strategy aims to elicit cytotoxic lymphocytes (CTL) against HIV, but this approach is undermined by the rapid mutation of HIV, which thereby escapes CTL control. Alloimmunity has been found to be protective in vertical transmission from infected mothers to their babies, in alloimmunization of women with their partners’ mononuclear cells, and in monkeys immunized with SIV grown in human T-cells. Vaginal mucosal immunization, as a result of unprotected sex with a regular partner, induced in vitro protection against HIV infection, and this was confirmed in macaques. The second type of natural protection is found in persons with the homozygous 32 CCR5 mutation, a 32-base-pair deletion of the CCR5 gene, which results in a lack of cell-surface expression of CCR5, which is associated with an increase in CC chemokines and the development of CCR5 antibodies. These two ‘experiments of nature’ have been used to develop vaccine strategies—first, in vaginal immunization of macaques with CCR5 peptides, in addition to HIV envelope (env) and SIV core (gag) antigens, all of which were linked to the 70-kD heat-shock protein (HSP70); and second, in mucosal allo-immunization of macaques, which also gave rise to in vitro protection from infection. Immunization with this vaccine elicited serum and vaginal IgG and IgA antibodies, IFN- and IL-12-producing cells, and increased concentrations of CCL-3 and CCL-4. Vaginal challenge with a simian immunodeficiency virus engineered to carry a human envelope protein (SHIV 89.6) showed significant clearance of SHIV in the immunized macaques. This platform strategy will now be developed to activate the co-stimulatory pathways with the aim of enhancing the primary allogeneic and CCR5-directed responses which are involved in natural protection against HIV infection. Abbreviations: IFN-, gamma interferon; IL-12, interleukin 12; MIP-1 ,β, Macrophage inflammatory protein-1; RANTES, Regulated on activation normal T-cell expressed and secreted; SDF-1, stromal-derived factor 1; SIV, simian immunodeficiency virus; and SHIV, engineered SIV carrying a human envelope protein.

The Effects of HIV Infection on Oral Mucosal Immunity

Challacombe, S.J., Naglik, J.R. — 2006-04-01

Oral mucosal infections, especially candidiasis, are a feature of HIV disease, suggesting that compromised mucosal immunity within the oral cavity is a consequence of the viral infection. However, how this mucosal immunity is compromised and at what stage of HIV infection this occurs are unclear. Better understanding of the protection of the oral cavity against infection has allowed us to gain some insight into the local consequences of HIV infection. From a humoral perpective, IgA2 subclasses are reduced in HIV infection in saliva, and total secretory IgA levels are reduced in later disease. Similarly, mucosal antibody responses appear near normal in early HIV infection but reduced in AIDS. There is now convincing evidence that salivary IgA can be neutralizing to HIV 1 and HIV 2, as well as block epithelial transmigration. Oral cellular immunity is also affected by HIV infection. Transmission of HIV from one oral cell type to another appears to be confirmed by work showing that HIV can bind to or infect epithelial cells, Langerhans cells, and other mucosal cells. CXCR4 tropic (via GalCer and CXCR4) and dual tropic HIV strains have been shown to be able to infect normal human oral keratinocytes (NHOKs), and infectious HIV virions can also be conveyed from NHOKs to activated peripheral blood lymphocytes, suggesting a potential role of oral epithelial cells in the transmission of HIV infection. There is evidence of up-regulation of various receptors, including HIV receptors, on the surface of oral epithelium, and the epithelium may become more permeable. HIV may exploit this antigen uptake mechanism to cross epithelial barriers during co-infection with damage-inducing pathogens such as Candida. Immune responsiveness to many of the co-pathogens associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR), and recognition of a single pathogen can involve activation of multiple TLRs. Consequently, TLR-pathogen interactions could play an indirect but major role in regulating HIV-associated disease in the oral cavity. Thus, HIV infection appears to have both direct and indirect effects on oral mucosal immunity, affecting both cellular and humoral immunity as well as both specific and innate immunity.

Dendritic Cells and HIV Infection: Activating Dendritic Cells to Boost Immunity

Teleshova, N., Kenney, J., Robbiani, M. — 2006-04-01

Dendritic cells (DCs) are white blood cells that coordinate innate and adaptive immunity. They are distributed within epithelia and mucosal-associated lymphoid tissues, positioned to entrap incoming pathogens or vaccines. Human immunodeficiency virus (HIV) and the non-human primate equivalent (SIV) exploit DCs to amplify infection, underscoring the need to harness strategies that promote presentation of virus by DCs to stimulate potent anti-viral immunity instead of virus transmission. Two main subsets of DCs need to be considered: myeloid (MDC) and plasmacytoid (PDC) subsets. Using the SIV-macaque system to advance oral vaccine research, we examined macaque PDC and MDC biology, identifying ways to activate DCs and boost antiviral immunity. Immunostimulatory oligodeoxyribonucleotides (ISS-ODNs) stimulated PDC/MDC mixtures to up-regulate co-stimulatory molecule expression and to secrete both IFN- and IL-12. Additionally, ISS-ODNs augmented SIV-specific IFN-responses induced by virus-bearing DCs. ISS-ODN-driven DC activation is being pursued to improve oral/nasopharyngeal mucosal vaccines and therapies against HIV.

Role of Human {beta}-defensins in HIV Infection

Weinberg, A., Quinones-Mateu, M.E., Lederman, M.M. — 2006-04-01

Mechanisms of resistance to HIV-1 infection in the human oral cavity are incompletely understood. While salivary components have been implicated in protection, there is growing evidence that human beta-defensins (hBDs), originating in oral epithelial cells, may be playing an important role in the prevention of HIV infection. New antiviral, chemotactic, and immunosurveillance properties are being attributed to hBDs, which are small cationic antimicrobial innate response molecules expressed in mucosal epithelium. Inducible hBDs are always expressed in normal oral epithelium, a property not shared by other mucosal barriers. Data reviewed in this paper demonstrate that: (1) HIV-1 X4 and R5 phenotypes induce hBD-2 and -3 mRNA in normal human oral epithelial cells; (2) hBD-2 and -3 inhibit HIV-1 infection by both viral strains, with greater activity against X4 viruses; and (3) this inhibition is due to a direct interaction with virions and through modulation of the CXCR4 co-receptor. These properties may be exploited as strategies for mucosal protection against HIV-1 transmission.

Oral Mucosal Expression of HIV-1 Receptors, Co-receptors, and {alpha}-defensins: Tableau of Resistance or Susceptibility to HIV Infection?

Cutler, C.W., Jotwani, R. — 2006-04-01

The basic premise of whether transmission of HIV-1 through the oral mucosa actually occurs, and through what route, is a topic of intense interest. Our work has focused on HIV-1 receptors/co-receptors and -defensin-1 in situ in human gingiva. Regardless of HIV-1 infection, the role that C-type lectin receptors might play in periodontal pathogenesis is of great interest. We have shown that the gingival lamina propria, when inflamed, becomes increasingly infiltrated with DC-SIGN+MR+ dermal dendritic cells (DDCs), while the inflamed epithelium shows a decrease in Langerin+ Langerhans cells (LCs). Moreover, DDCs and LCs contribute to the mature CD83+ DC pool in situ, and form immune conjugates with CD4+ T-cells in the lamina propria (Jotwani and Cutler, 2003). This raises the intriguing possibility that oral mucosal DCs may be involved in HIV-1 transfer to T-cells in situ. However, this possibility is tendered by the challenges faced by the virus in gaining access to oral mucosal immune cells, including their ability to survive the salivary defenses, cross the mucosal barrier, resist inactivation by -defensins, and overcome the paucity of co-receptor CCR5 in (healthy) oral mucosa (i.e., required for productive infection [Jotwani et al., 2004]). To date, there is little evidence of direct infection by HIV-1 of oral mucosal DCs/T cells and other cells in situ. Abbreviations used in this paper: CP, chronic periodontitis; CCR5, chemokine receptor 5; CXCR4, C-X-C receptor 4; DCs, dendritic cells; DC-SIGN, DC-specific ICAM-3 grabbing non-integrin; DDC, dermal dendritic cells; LCs, Langerhans cells; LP, lamina propria; MR, mannose receptor.

Differential Mucosal Susceptibility in HIV-1 Transmission and Infection

Moutsopoulos, N.M., Greenwell-Wild, T., Wahl, S.M. — 2006-04-01

HIV infection occurs primarily through mucosal surfaces, indicating that protection at mucosal sites may be crucial in prevention and treatment. The host innate and adaptive immune elements provide a level of protection, which differs between mucosal compartments, and appears to be most successful in the oral environment, where transmission is rare. In addition to the distinct oral mucosal architecture and cellular constituents, oral fluids, unlike other mucosal secretions, are rarely a vehicle for HIV infection. Multiple soluble factors may contribute to this antiviral activity, including neutralizing antibodies, secretory leukocyte protease inhibitor (SLPI), antiviral peptides such as defensins and cystatins, glycoproteins including thrombospondin and lactoferrin, and complement components. Understanding the antiviral activities of these and other potential resistance factors is becoming increasingly important in attempts to design treatments in the era of HAART resistance. In this regard, the mechanism of anti-HIV action of SLPI has recently been further elucidated by the discovery of its binding protein/receptor, which plays a key role in the infection of macrophages and may consequently be a novel therapeutic target. Continued elucidation of the unique features of mucosal HIV immunology is essential for understanding HIV pathogenesis and for developing effective vaccines and therapeutics.

Oral Lesions of HIV Disease and HAART in Industrialized Countries

Hodgson, T.A., Greenspan, D., Greenspan, J.S. — 2006-04-01

The epidemiology of HIV-related oral disease in industrialized nations has evolved following the initial manifestations described in 1982. Studies from both the Americas and Europe report a decreased frequency of HIV-related oral manifestations of 10–50% following the introduction of HAART (highly active antiretroviral therapy). Evidence suggests that HAART plays an important role in controlling the occurrence of oral candidosis. The effect of HAART on reducing the incidence of oral lesions, other than oral candidosis, does not appear as significant, possibly as a result of low lesion prevalence in industrialized countries. In contrast to other oral manifestations of HIV, an increased prevalence of oral warts in patients on HAART has been reported from the USA and the UK. HIV-related salivary gland disease may show a trend of rising prevalence in the USA and Europe. The re-emergence of HIV-related oral disease may be indicative of failing therapy. A range of orofacial iatrogenic consequences of HAART has been reported, and it is often difficult to distinguish between true HIV-related oral disease manifestations and the adverse effects of HAART. A possible association between an increased risk of oral squamous cell carcinoma and HIV infection has been suggested by at least three epidemiological studies, with reference to the lip and tongue. These substantial and intensive research efforts directed toward enhancing knowledge regarding the orofacial consequences of HIV infection in the industrialized nations require dissemination in the wider health care environment.

Oral Lesions in HIV Infection in Developing Countries: an Overview

Ranganathan, K., Hemalatha, R. — 2006-04-01

HIV infection is a major global health problem affecting developing and developed countries alike. Oral lesions that are associated with this disease are important, since they affect the quality of life of the patient and are useful markers of disease progression and immunosuppression. Oral lesions in HIV infection have been well-documented in developed countries, but there are fewer reports on oral lesions from developing countries. Oral candidiasis is the most common opportunistic infection seen in all continents. Kaposi’s sarcoma has been reported only from Africa and Latin America, while histoplasmosis and penicilliosis were reported in patients with advanced disease from Thailand. HIV-associated salivary gland disease has a high prevalence in Africa and Latin America, especially in the pediatric group. It is clear that there are considerable regional variations in the oral manifestations of HIV infection, depending both on the populations studied and on the clinical expertise available, among other factors. Well-designed and -documented studies are necessary for the correct assessment of the nature and magnitude of the problem in developing countries, if oral health measures are to be effectively formulated for the HIV-infected.

Skin Lesions: Mirror Images of Oral Lesion Infections

Phanuphak, N. — 2006-04-01

Skin lesions can be the presenting signs for HIV disease and are among the most prevalent manifestations throughout the course of HIV disease. Correlation of skin diseases and HIV disease staging has long been recognized and used to guide medical management in resource-limited settings. The purpose of this paper is to give a review of common skin infections presented in HIV-infected patients. Common skin infections presenting in HIV-infected patients include viral, fungal, mycobacterial, and bacterial infections, along with skin infestation. Key diagnostic points correlate with certain HIV disease staging for many skin diseases. These can help facilitate appropriate diagnosis and referral by health care personnel when treating HIV-infected patients who have skin lesions. Knowledge of common skin manifestations found in HIV-infected patients is essential for all health care personnel who work in the HIV field. Most skin infections presenting in HIV-infected patients can be treated effectively if the correct diagnosis and appropriate referral are made promptly.

Implications of HIV Disease for Oral Health Services

Robinson, P.G. — 2006-04-01

This paper, by means of a quality framework, reviews health services research in relation to people with HIV infection. The relevance of oral health care services to people’s needs is considered in terms of the goal of health services to reduce the burden of disease on the everyday life of the population. Dental services may therefore have a role in primary prevention in the HIV epidemic, passing on information about HIV and promoting health through the early diagnosis and treatment of oral disease. Effectiveness research of oral health care in HIV assesses the usefulness of oral diagnosis, whether care is safe, and whether treatment is clinically effective. Few data are available on the efficiency of services. People with HIV still have problems accessing dental care, due to the volume of care available in relation to their need and acceptability of care. Access problems in the US are compounded by social inequality. Health services research data are particularly sparse in resource-poor countries, and there is a need to translate the available information into treatment guidelines appropriate to these settings. The research community and funding agencies should place greater emphasis on the quality of oral health services for people with HIV.

Candida-Host Interactions in HIV Disease: Relationships in Oropharyngeal Candidiasis

Fidel, P.L. — 2006-04-01

Oropharyngeal candidiasis (OPC) caused by the commensal organism, Candida albicans, is the most common oral infection in HIV disease. Although cell-mediated immunity (CMI) by Th1-type CD4⁺ T-cells is considered the predominant host defense mechanism against OPC, other systemic or local immune mechanisms are critical when blood CD4⁺ T-cells are reduced below a protective threshold. For example, the Th cytokine profile in saliva may influence resistance or susceptibility to OPC. In OPC lesions, CD8⁺ T-cells become accumulated at the lamina propria-epithelium interface, suggesting some role for CD8⁺ T-cells against OPC. However, the absence of CD8⁺ T-cells close to Candida at the outer epithelium indicates that susceptibility to OPC involves a dysfunction in the CD8⁺ T-cells or in the micro-environment. Further evaluation of the buccal mucosa lesion showed that CD8 T-cell-associated cytokine and chemokine mRNA is increased compared with buccal mucosa from lesion-negative matched controls. The majority of CD8⁺ T-cells present possess the β T-cell receptor and several homing receptors (i.e., ₄β₇, ₄β₁, _eβ₇). While several adhesion molecules are similar in OPC⁺ vs. OPC^– persons, E-cadherin is reduced in the tissue of OPC⁺ persons. These results support evidence for a role for CD8⁺ T-cells against OPC, but suggest that a putative dysfunction in mucosal T-cell trafficking may be associated with susceptibility to infection. Similar levels of Candida-specific antibodies in persons with and without OPC confirmed a limited role for humoral immunity. Finally, oral epithelial cells inhibit the growth of Candida in vitro in a static rather than a cidal manner. Clinically, oral epithelial cell anti-Candida activity is reduced in HIV⁺ persons with OPC, compared with controls. The mechanism of action includes a strict requirement for cell contact by an acid-labile moiety on intact, but not necessarily live, epithelial cells, with no role for soluble factors. Taken together, host defense against OPC involves several levels of activity. The status and efficiency of local host defenses when blood CD4⁺ T-cells are not available appear to play a role in protection against or susceptibility to OPC.

Conceptual Emergence of Human Herpesvirus 8 (Kaposi's Sarcoma-associated Herpesvirus) as an Oral Herpesvirus

Teo, C.G. — 2006-04-01

Recognition of the various clinico-epidemiologic forms of Kaposi’s sarcoma, a disease putatively caused by an infectious agent, did not provide ready clues as to how that agent might be transmitted, although fecal and sexual routes were implicated. Application of serologic and genome-detection assays, and cell-culture studies following the identification of human herpesvirus 8 as the causative agent now implicate that virus as one that is orally shed. While oral transmission of the virus might account for the viral endemicity in Africa and Mediterranean countries, why it is particularly prevalent among male homosexuals in the West remains more difficult to explain. Such explanation may be sought from behavioral studies into the role saliva plays in sexual interactions.

Oral EBV and KSHV Infection in HIV

Webster-Cyriaque, J., Duus, K., Cooper, C., Duncan, M. — 2006-04-01

The gamma herpesviruses, Kaposi’s-sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are tightly associated with the development of AIDS-associated oral disease and malignancy during immune suppression. The objective of this investigation was to characterize oral infection and pathogenesis in healthy and immune-suppressed individuals. To characterize oral EBV and KSHV infection, we examined throat washings and oral epithelial cells from HIV-positive and HIV-negative individuals. Quantitative/real-time polymerase-chain-reaction (PCR) assays, transmission electronmicroscopy, immunostaining, and sequence analysis were used to identify viral infection. Virus was isolated from throat-wash samples and was used to infect epithelial and lymphoid cell lines. We detected EBV and KSHV in the oral cavity in healthy and immune-suppressed individuals. Viral strain analysis of KSHV K1 in multiple clones from the oral cavities of healthy persons and immunosuppressed patients detected several strains previously detected in KS lesions, with minor strain variation within individuals. Immunoelectron microscopy for multiple viral antigens detected consistent expression of viral proteins and oral epithelial specimens. In oral epithelial cells infected with wild-type KSHV in vitro, the K8.1 glycoprotein associated with lytic KSHV infection was detected in both primary and telomerase immortalized oral epithelial cultures by 24 hours post-infection. Virions were detected, subsequent to infection, by scanning electron microscopy. Oral epithelial cells were also infected in vitro with wild-type EBV originating from throat washes. Analysis of these data suggests that, like EBV, KSHV infection is present in the oropharynx of healthy individuals, is transmissible in vitro, and may be transmitted by saliva.

Cytomegalovirus Co-infection in AIDS-associated Oral Kaposi's Sarcoma

Meer, S., Altini, M. — 2006-04-01

The increasing appearance of AIDS-associated oral Kaposi’s sarcoma (KS) in South Africa may be ascribed to the later start of the HIV epidemic, more patients reaching stages III and IV, and the inaccessibility of most patients to anti-retroviral therapy. The objective of this study was to demonstrate cytomegalovirus (CMV) co-infection in oral KS and to consider its possible significance. We reviewed 20 cases of oral KS in known HIV-positive patients without active CMV disease. HHV8 PCR and CMV immunohistochemistry were performed. HHV8 DNA was present in all cases. CMV inclusions were detected in five cases. The significance of CMV co-infection in oral KS is unclear. The inclusions suggest active infection, although there is no evidence to support CMV in the pathogenesis of KS. Nonetheless, it is vital that physicians be alerted to active CMV infection, so that timely intervention and careful observation can be instituted, ensuring early diagnosis and treatment.

Biology of HPV in HIV Infection

Palefsky, J. — 2006-04-01

HIV-positive men and women are at increased risk of anogenital and oral HPV infection. The risks for HPV-associated high-grade intra-epithelial neoplasia (IN) and cancer are also increased. The prevalence of oral, anal, and cervical HPV infection in HIV-positive individuals compared with HIV-negative individuals increases with progressively lower CD4+ levels, as does incident high-grade IN. In contrast to IN, development of cancer is not related to lower CD4+ level. With increasing grades of IN and cancer, the proportion of tissues with copy-number abnormalities (CNA) increases, with one of the most common genetic changes being amplification of chromosome 3q. The presence of CNA is associated with the integration of HPV DNA into the host genome, with loss of HPV E2 and/or E2 rearrangement. This suggests a link between CNA and increased HPV-induced chromosomal instability mediated through de-repressed E6 and E7 expression consequent to loss of functional E2 protein. In addition, epigenetic changes occur with increasing frequency in high-grade IN and cancer, such as hypermethylation leading to down-regulation of potential tumor suppressor genes. Analysis of these data together suggests that immune suppression plays a more prominent role in the earlier stages of HPV-associated disease, up to and including incident high-grade IN. Persistent high-grade IN and development of cancer may be more strongly related to the cumulative effect of HPV-associated genetic instability and the resulting host genetic changes. There are few data to suggest a direct role for HIV in the pathogenesis of HPV-associated neoplasia, but HIV-associated attenuation of HPV-specific immune responses may allow for persistence of high-grade IN and sufficient time for accumulation of genetic changes that are important in progression to cancer.

(A1) Identification of Oral Health Care Needs in Children and Adults, Management of Oral Diseases

Hodgson, T.A., Naidoo, S., Chidzonga, M., Ramos-Gomez, F., Shiboski, C. — 2006-04-01

The workshop considered five questions reviewing the identification of international oral health care needs of children and adults, and the management of oral diseases in resource-poor countries: (1) What is the role of the dental profession in the management of the HIV-infected individual? (2) Identifying health care needs-What are the epidemiology and disparities of HIV-associated oral lesions in children from different continents? (3) How effective is HIV treatment in controlling oral diseases? (4) Could we develop basic inexpensive oral and dental care protocols for economically deprived HIV-infected patients? and (5) What is the best method of arranging resources to meet the oral health care needs of people with HIV disease? The consensus of the workshop participants was that there is a need to re-target research efforts to non-established market economy countries and prioritize research in these regions to children with HIV disease. It will be important to assess commonalities and variations in oral health needs across geographical and cultural boundaries, and research efforts should be centralized in resource-poor countries to support multi-center longitudinal standardized studies. It is essential that oral health research be integrated into other health care research programs, to make these research priorities and public health initiatives feasible.

(A2) Oral Health and General Health

Johnson, N.W., Glick, M., Mbuguye, T.N.L. — 2006-04-01

The interactions between oral and systemic health are bi-directional and complex, involving many pathways. Regarding health as not merely the absence of disease, but as a state of total well-being, these interactions profoundly influence the progress of many diseases, and the quality of life and economic performance of HIV-infected individuals and populations. The evidence base for specific interactions is currently weak, partly because few good-quality studies have been published, partly because of the naïveté of the instruments currently available for recording these interactions and their inherent complexity. Recording quality of life should be a fundamental aspect of all future studies. The most significant conclusion of this Workshop is the need for all involved in oral health research and oral health care to be seen as, and to act as, essential partners in comprehensive care for whole patients and communities.

(A3) HIV Phenotypes, Oral Lesions, and Management of HIV-related Disease

2006-04-01

Workshop participants discussed: the role of HIV subtypes in disease; the treatment of oral candidiasis; the relationship between and among viral load, CD4⁺ counts, oral candidiasis and oral hairy leukoplakia, pigmentation; and the development of a reliable oral index to predict disease progression. Regarding HIV, the literature revealed that Type I (HIV-I), in particular group M, is involved in the majority (90%) of documented infections, and groups N and O to a lesser extent. Viral envelope diversity led to the subclassification of the virus into nine subtypes, or clades—A–D, F-H, J, and K—each dominating in different geographical areas. HIV-2, currently occurring mostly in West Africa, appears to be less virulent. No evidence could be produced of any direct impact of type, subtype, or clade on oral lesions, and participants believed that further research is not feasible. Oral candidiasis in patients from resource-poor countries should be prevented. When the condition does occur, it should be treated until all clinical symptoms disappear. Oral rinsing with an antimicrobial agent was suggested to prevent recurrence of the condition, to reduce cost, and to prevent the development of antifungal resistance. Lawsone methyl ether, isolated from a plant (Rhinacanthus nasutus leaves) in Thailand, is a cost-effective mouthrinse with potent antifungal activity. Evidence from a carefully designed prospective longitudinal study on a Mexican cohort of HIV/AIDS patients, not receiving anti-retroviral treatment, revealed that the onset of oral candidiasis and oral hairy leukoplakia was heralded by a sustained reduction of CD4⁺, with an associated sharp increase in viral load. Analysis of the data obtained from a large cohort of HIV/AIDS patients in India could not establish a systemic or local cause of oral melanin pigmentation. A possible explanation was a dysfunctional immune system that increased melanin production. However, longitudinal studies may contribute to a better understanding of this phenomenon. Finally, a development plan was presented that could provide a reliable prediction of disease progression. To be useful in developing countries, the index should be independent of costly blood counts and viral load.

(B1) Candida and Mycotic Infections

Coogan, M.M., Fidel, P.L., Komesu, M.C., Maeda, N., Samaranayake, L.P. — 2006-04-01

Oral candidiasis (OC) is the most common mucosal manifestation of HIV infection. This workshop examined OC and other mycoses associated with HIV infection. Historically, blood CD4 cell numbers were the primary prognosticator for the development of OC. However, a study that statistically evaluated the predictive role of HIV viral load vs. CD4 cell counts revealed viral load to be a stronger predictor for OC. The role of biofilms and antifungal resistance in recalcitrant OC is unclear at present. In general, micro-organisms including yeasts in biofilms are more resistant to antifungals than their planktonic counterparts. When the remaining organisms are eliminated, the few resistant organisms may not be problematic, because they are present in low numbers. Unusual exotic mycoses in HIV-infected patients are more common in patients from the developing than the developed world. These infections may be recurrent and recalcitrant to therapy, be present in multiple and uncommon sites, increase with the progression of HIV disease, and may play a role similar to that of the more common mycoses. Typing and subtyping of yeasts are probably not critical to the clinical management of candidiasis caused by Candida albicans and non-albicans strains, including C. dubliniensis, because it is responsive to antifungal therapy. C. glabrata is probably the only exception. The presence of oral thrush in infants younger than 6 months of age is associated with an increased post-natal transmission risk of HIV infection. Thus, perinatal retroviral therapy should be combined with the treatment of oral thrush to prevent the post-natal acquisition of HIV.

(B2) Periodontal Diseases and Other Bacterial Infections

Umadevi, M., Adeyemi, O., Patel, M., Reichart, P.A., Robinson, P.G. — 2006-04-01

The workshop addressed the following questions with respect to periodontal diseases and bacterial infections seen in HIV infection: (1) What is linear gingival erythema? Is it prevalent only in HIV disease? A crude Delphi technique was used to ascertain whether LGE existed, but a consensus could not be reached. It was agreed that a diagnosis of LGE should be considered only if the lesion persists after removal of plaque in the initial visit. (2) Do periodontal pockets contribute to viremia in HIV infection? At present, the data are not available to answer this question. (3) Do anti-viral drugs reach the sulcular fluid in significant concentrations? No one at the workshop was aware of data that could answer this question. (4) Does concurrent tuberculosis infection modify the oral manifestations of HIV infection? Though analysis of data from the developing countries does suggest an association between tuberculosis and oral candidiasis, more data and multivariate analysis considering immunosuppression as a confounding factor are necessary, for any conclusions to be derived. (5) What pathogens are involved in periodontal diseases in HIV infection? Periodontal disease may be initiated by conventional periodontal pathogens. But the progression and tissue destruction depend upon the presence of typical and atypical micro-organisms, including viruses, their by-products, increased secretion of potentially destructive inflammatory mediators, and overwhelming host response. (6) How can we diagnose the diseases seen in HIV infection? The answer can be obtained only with data from controlled and blinded studies. It is necessary to design collaborative multi-center longitudinal studies. The results obtained from such large sample sizes can contribute eventually to interpretation of the outcome.

(B3) Markers of Immunodeficiency and Mechanisms of HAART Therapy on Oral Lesions

Flint, S.R., Tappuni, A., Leigh, J., Schmidt-Westhausen, A.-M., MacPhail, L. — 2006-04-01

Highly active anti-retroviral therapy (HAART) has revolutionized the treatment and prognosis of HIV disease and AIDS in those who can take advantage of the treatment. There are currently 20 different anti-retroviral drugs in 4 different classes that are used in specific combinations. Suppression of HIV replication and immune reconstitution are goals of therapy. Since the prevalence of some easily detectable oral manifestations of HIV/AIDS (OMHIV/AIDS) decreases with HAART, it has been suggested that they might be clinically useful surrogate markers of HAART efficacy and immune status. This might be particularly useful if their recurrence presaged or accompanied HAART failure. To date, there has been little work in this area, but its potential value to the clinical management of HIV/AIDS is apparent, especially if frequent measures of viral load and CD4 cell counts are not readily available. However, the usefulness of OMHIV/AIDS as signals for HAART failure is complicated by three phenomena: the immune reconstitution syndrome, the similarity of some adverse reactions of HAART to OMHIV/AIDS, and the direct inhibitory effect of HAART medications on some OMHIV/AIDS (e.g., inhibition of oral candidosis by protease inhibitors). This workshop considered the current evidence and proposed pertinent research questions.

(C2) Saliva, Breast Milk, and Mucosal Fluids in HIV Transmission

Page-Shafer, K., Sweet, S., Kassaye, S., Ssali, C. — 2006-04-01

The oral environment has received various amounts of attention in association with HIV infection and pathogenesis. Since HIV infection occurs through mucosal tissue, oral factors—including tissue, fluids, and compartments—are of interest in furthering our understanding of the diagnosis, infectivity, transmission, and pathogenesis of disease. This report reviews: (1) HIV testing and diagnoses with oral fluids; (2) post-natal acquisition of HIV in association with breast-feeding from HIV-positive mothers; and (3) oral sex and HIV transmission. In the first, we examine how oral fluids are used to detect HIV infection and review current consensus on the role of salivary molecules as markers for immunosuppression. Second, lactation-associated HIV acquisition is reviewed, with special consideration of emerging issues associated with the impact of anti-retroviral therapies. Last, we consider current data on the risk of HIV infection in association with oral sex. Investigation of these diverse topics has a common goal: understanding how HIV presents in the oral environment, with an aim to rapid and accessible HIV diagnosis, and improved prevention and treatment of infection.

(C3) The Oral Epithelial Cell and First Encounters with HIV-1

Herzberg, M.C., Weinberg, A., Wahl, S.M. — 2006-04-01

The oral epithelium is the site of first exposure of HIV-1 to host tissues during oral sex with an infected partner or through breast-feeding by an infected mother. Although the oral epithelium is distinguishable by its apparent resistance, the mucosal surfaces represent a primary target of HIV-1. After oral exposure and swallowing, infection is detected prominently in the gastrointestinal tract, which becomes depleted of CD4⁺ T-cells. The oral cavity and palatine tonsils appear to resist infection and transfer to susceptible lymphoid cells in the lamina propria by local anti-HIV-1 mechanisms. In some cases, expression of these antiviral mechanisms increases after exposure to HIV-1. During primary exposure and before seroconversion, based on limited in vitro and primate data, a window of opportunity for capture of HIV-1 by the oral epithelium may exist. After seroconversion, the risk of infectious HIV-1 appearing in saliva is negligible. This report considers evidence that oral epithelium has the potential both to enable and to resist infection by HIV-1.

Abstracts

2006-04-01

Oral Research in Primary Care

Burke, F.M., O'Mullane, D. — 2005-12-01

Experience of Clinical Trials in General Dental Practice

Clarkson, J. — 2005-12-01

Use of Dental Service Data to Inform Research and Policy

Whelton, H., O'Mullane, D., Burke, F.M., Woods, N., Cronin, M. — 2005-12-01

Evaluating Restorative Materials and Procedures in Dental Practice

Burke, F.J.T. — 2005-12-01

The Data Stations Project of the Dutch Dental Association

Bruers, J.J.M., Zeegers, G.L.A.M. — 2005-12-01